Pancreatología PDF

Accepted Manuscript
Guidelines for the understanding and management of pain in chronic pancreatitis
Asbjrn M. Drewes, Stefan A.W. Bouwense, Claudia M. Campbell, Gralp O.

Ceyhan, Myriam Delhaye, Ihsan Ekin Demir, Pramod K. Garg, Harry van Goor,
Christopher Halloran, Shuiji Isaji, John P. Neoptolemos, Sren S. Olesen, Tonya
Palermo, Pankaj Jay Pasricha, Andrea Sheel, Tooru Shimosegawa, Eva Szigethy,
David C. Whitcomb, Dhiraj Yadav
PII: S1424-3903(17)30515-X
DOI: 10.1016/j.pan.2017.07.006
Reference: PAN 750
To appear in: Pancreatology
Received Date: 23 March 2017

Revised Date: 26 June 2017
Accepted Date: 11 July 2017
Please cite this article as: Drewes AsbjM, Bouwense SAW, Campbell CM, Ceyhan GO, Delhaye M,
Demir IE, Garg PK, van Goor H, Halloran C, Isaji S, Neoptolemos JP, Olesen SS, Palermo T, Pasricha
PJ, Sheel A, Shimosegawa T, Szigethy E, Whitcomb DC, Yadav D, for the Working group for the
International (IAP APA JPS EPC) Consensus Guidelines for Chronic Pancreatitis, Guidelines for
the understanding and management of pain in chronic pancreatitis, Pancreatology (2017), doi: 10.1016/
j.pan.2017.07.006.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Guidelines for the understanding and management of pain in

chronic pancreatitis
Recommendations from the Working Group for the International Consensus Guidelines for Chronic
Pancreatitis in collaboration with the International Association of Pancreatology, American
Pancreatic Association, Japan Pancreas Society and European Pancreatic Club
PT
Asbjrn M Drewes1, Stefan A W Bouwense2, Claudia M Campbell3, Gralp O Ceyhan4, Myriam
Delhaye5, Ihsan Ekin Demir4, Pramod K Garg6, Harry van Goor2, Christopher Halloran7, Shuiji
Isaji8, John P Neoptolemos7, Sren S Olesen1, Tonya Palermo9, Pankaj Jay Pasricha10, Andrea
RI
Sheel7, Tooru Shimosegawa11, Eva Szigethy12, David C Whitcomb13 & Dhiraj Yadav13, for the
Working group for the International (IAP APA JPS EPC) Consensus Guidelines for Chronic
SC
Pancreatitis
1. Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital,
U
Denmark
2. Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
AN
3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
4. Department of Surgery, Klinikum rechts der Isar, Technische Universitt Mnchen, Munich, Germany
5. Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
6. Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
M
7. Institute of Translational Medicine, University of Liverpool, United Kingdom

8. Department of Surgery, Mie University Graduate School of Medicine, Japan
9. Seattle Children's Hospital Research Institute, Washington School of Medicine, USA
D
10. Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, USA
11. Department of Gastroenterology. Tohoku University Graduate School of Medicine, Japan
TE
12. Visceral Inflammation and Pain Center, Division of Gastroenterology, University of Pittsburgh and UPMC,
Pittsburgh, Pennsylvania, USA
13. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh,
Pennsylvania, USA
EP
Key words: Chronic pancreatitis; Pain treatment

C
Short title: Pain management

AC
Correspondence:
Professor Asbjrn Mohr Drewes, MD, Ph.D., D.M.Sc.
Centre for Pancreatic Diseases & Mech-Sense
Department of Gastroenterology and Hepatology
Clinical Institute, Aalborg University Hospital
Mlleparkvej, 9000-Aalborg, Denmark
amd@rn.d
ACCEPTED MANUSCRIPT
Abstract
Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrent or
chronic inflammation, local complications or neurogenic mechanisms with corresponding changes in the
nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reduce quality of
PT
life in patients with CP. Assessment of pain follows the guidelines for other types of chronic pain, where the
multidimensional nature of symptom presentation is taken into consideration. Quantitative sensory testing
RI
may be used to characterize pain, but is currently used in a research setting in advanced laboratories.
SC
For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs with
increasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be strongly
U
advised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopic
AN
treatment can be used in patients with evidence of ductal obstruction and may be combined with
extracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the main
M
pancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidisciplinary
approach to chronic pain management particularly when psychological impact is experienced. Surgery
D
should be considered early and after a maximum of five endoscopic interventions. The type of surgery
TE
depends on morphological changes of the pancreas. Long-term effects are variable, but high success rates
have been reported in open studies and when compared with endoscopic treatment. Finally, neurolytical
EP
interventions and neuromodulation can be considered in difficult patients.

C
AC
2
ACCEPTED MANUSCRIPT
In 2016, John P Neoptolemos, David C Whitcomb and Tooru Shimosegawa embarked on a joint venture to
produce the first truly International Guidelines on chronic pancreatitis (CP) with endorsement from the four
International Societies and support from their respective Presidents and members in general. Although
different guidelines exist such as the recent European consensus (1), the aim was to create a fresh clinical
approach to the most important complications of CP; not only to assist a more pragmatic basis for patient
PT
diagnosis and management, but also to help accelerate the assessment and hence the development of newer
RI
therapies. The guidelines follow a new mechanistic definition of chronic pancreatitis and conceptual model
of disease initiation and progression(2), which has been adopted by major international societies. Producing
SC
guidelines on CP is unquestionably a considerable task. Therefore the core committee for the working group
decided to divide the work into more manageable sections. Each section focused on the key topics of CP,
U
which were felt would benefit from consensus statements. The core committee identified International
AN
experts to ensure multidisciplinary representation from most regions of the world, and they were invited to
contribute work to their respective areas. Calls for volunteers to participate in the process were also
M
circulated around the four International Societies.
Prior to the process starting, the core committees were asked to vote on their preferred system for rating the
D
quality evidence, which would be used as the basis for the International CP guideline recommendations. The
TE
consensus was in favor of adopting a GRADE (Grading of Recommendations Assessment, Development,
and Evaluation) approach for topics lending themselves to evidence based statements. The guideline
EP
development process evolved over several milestone meetings at subsequent society conferences hosted
throughout 2016.
C
AC
The members of the Pain Management Working Group were appointed to represent worldwide specialists in
treatment of pancreatic pain with representatives from gastroenterology, endoscopy, surgery and
psychiatry/psychology. This was done to ensure an appropriate balance between the different regions and
specialties in order to achieve the most comprehensive evaluation and recommendations. AMD was
appointed as chairman of the group. First the following questions (Q) thought to be the most urgent and
clinical relevant were made and authors assigned to answer them. These were (author initials in brackets):
3
ACCEPTED MANUSCRIPT
Q1. What is the natural history and burden of pain in CP (in relation to treatment)? (DY, CMC)
Q2. Are there different types of pain in CP? (PJP, SSO, ES)
Q3. Which methods are available to assess pancreatic pain and its response to treatment? (CMC, PJP)
Q4. What is the role of smoking and alcohol on pain treatment in CP? (ES, PKG)
Q5. Do enzymes and antioxidants influence pain in CP? (PKG, ES)
PT
Q6. How can analgesics be used to treat pain in CP? (SSO, AMD, ES)
RI
Q7. Is endoscopic therapy effective for pain treatment in CP? (MD, SI, SAWB)
Q8. Is ESWL effective for pain treatment in CP? (CH, MD)
SC
Q9. Are other treatments (psychological, neurolytical etc.) of value for pain treatment in CP? (HvG, ES, TP)
Q10. What is the optimal surgical approach to release pain in CP? (GOC, HvG, SAWB)
U
Q11. When is the optimal time for surgery in painful CP? (GOC, IED)
AN
Q12. How to manage pain "relapse" after surgery or endoscopy? (IED, SI)
Q13. What are the indications for referral to a specialist center for further investigation of pain (CH, DY)
M
The working group then provided a structured format for systematic reviews for the different questions, and
D
included instructions on how to evaluate the level of evidence and clinical implications according to the
TE
GRADE guidelines, as adapted for UpToDate (http://www.uptodate.com/home/grading-tutorial). In the
absence or limited availability of literature, the Pain Management Working Group decided if a
EP
recommendation would be included in the consensus report. The quality of evidence supporting the different
statements was graded as (i) high if there was very low probability of further research completely changing
C
the presented conclusions, (ii) moderate if further research may completely change the conclusions, (iii)
AC
low if further research is likely to change the presented conclusions completely. The term very low (iv)
could be used if new research will most probably change the presented conclusions completely; however, the
term was not used in the present work.
4
ACCEPTED MANUSCRIPT
The strength of the recommendation was classed as weak/conditional, strong or not applicable. This
took in to account the quality of evidence, the translation of evidence into clinical practice, and any relevant
uncertainties relating to population risk.
Finally, to gauge the level of objective support from the participating international expert panel, the members
PT
of the Pain Management Working Group voted using a nine-point Likert scale on their level of agreement
RI
with the recommendations and their GRADE score. Voting results were classified under agreement as
either; strong (80% of votes were 7 or above), conditional (65% of votes were 7 or above), and weak (<
SC
65% of votes were 7 or above).
All authors reviewed the final manuscript to ensure the general relevance and applicability of the
U
conclusions. The European Pancreatic Club conference in July 2016 hosted the first milestone meeting for
AN
the process of developing the International CP guidelines. AMD presented the outcomes of the Pain
Management Working Group to the meeting and the work is summarized in this manuscript.
M
In the present document, the recommendations are listed with a summary of the most relevant information
D
and references. However, due to word limits most information could not be included and the reader is
TE
encouraged to see the Appendix (www.xxx) where the full text and references are found.
EP
Q1. What is the natural history and burden of pain in chronic pancreatitis?
Abdominal pain is the most frequent symptom of CP. However, the severity, temporal nature, and natural
C
history of pain is highly variable (Quality assessment: moderate; Recommendation: strong; Agreement:
AC
strong)
While variation in disease estimates exist, the prevalence of CP has been approximated at ~50/100,000
population(3). Abdominal pain, alone or during episode(s) of acute exacerbation of pancreatitis, is the most
common symptom. Patients typically describe their pain as a dull, sharp or nagging sensation in the upper
abdomen, which can radiate to the back, and often presents after or worsened by food intake. In natural
5
ACCEPTED MANUSCRIPT
history studies, pain was observed as the initial presentation in ~75% of patients(4), and present during the
clinical course in 85-97%(47). Patients with early onset-disease and those with alcohol etiology are more
likely to have pain(4,5). According to the burn-out hypothesis, a majority of patients with chronic
pancreatitis achieve lasting pain-free status during the clinical course(5,8). This claim, however, has not been
substantiated by others, mainly due to persistence of pain symptoms in a significant fraction of patients with
PT
ongoing pain even after 10 or more years of disease(9). Naturally, CP is a major burden for patients and both
RI
pain intensity and the frequency of pain attacks have been shown to reduce quality of life
substantially(10,11).
SC
Q2. Are there different types of pain in CP and what does it mean for treatment?
U
Pain in CP remains poorly understood and inadequately correlated with neurobiological mechanisms. By
AN
definition, CP is characterized by inflammation but unlike other inflammatory disorders, there is a paucity of
therapeutic attempts targeting this particular aspect of pathophysiology. On the other hand, there are
M
striking changes in structure and function in both the peripheral and central nervous system in this
condition, lending plausibility to a maladaptive state that includes both neuropathic and dysfunctional pain.
D
In the absence of effective anti-inflammatory approaches, it is clearly important to focus on the alteration of
TE
function that accompanies these changes in the nociceptive system as a potential therapeutic target. (Quality
assessment: low; Recommendation: strong; Agreement: strong)

EP
An early approach to classifying pain in CP was made by Amman et al.(8) A-type pain pattern was seen
C
in patients with one or more discrete episodes of pain interspersed with pain-free intervals. Slightly less than
AC
half (44%) of patients also had B-type pain described as persistent (i.e. daily) pain over prolonged periods
of time and/or closely clustered exacerbations of severe pain. A later study demonstrated that clinical
outcomes were best predicted when intermittent (about 45% of patients) versus constant pain were
compared, thus echoing the earlier binary classification(10).
6
ACCEPTED MANUSCRIPT
Putative neurobiological causes of pain
Inflammation: It is intuitively appealing to suggest that a significant, if not major, type of pain in CP is
inflammatory in nature. Animal models hava also shown that inflammatory pain in CP is mechanistically
generally similar to other chronic inflammatory conditions. The expression of numerous algogenic factors is
altered in experimental models as well as in human pancreatic specimens. Some but not all of these factors
PT
and molecules have been shown to correlate with pain severity, although causation is not proven(1214). On
RI
the other hand, intermittent episodes of pain observed in patients correspond not always to a flare of
inflammation. Correspondingly, in a large prospective cohort study, there was no correlation between
SC
temporal pattern and the presence or absence of radiological evidence of inflammation or obstructive
pathology(10,15).
U
AN
Neuropathy: Animal models have provided convincing evidence that CP results in hypersensitivity of pain
responses to pancreatic stimulation, associated with impressive sensitization of the primary nociceptive
M
neuron with specific electrophysiological and molecular changes. The models also suggest a component of
central sensitization including potential roles for spinal glial activation and descending inhibitory pathways
D
(1618). Correspondingly, patients with severe CP have lower pain thresholds and expanded pain referral
TE
areas than patients with moderate CP or healthy volunteers, which is a reflection of spinal
sensitization(19,20). Alterations in descending inhibitory influences on spinal nociceptive neurons have also
EP
been shown in humans(1922). Finally, electroencephalographic and imaging findings in patients with CP
similarly show functional changes suggesting a maladaptive pain response(20,2326).

C
AC
Q3. Which methods are available to assess pancreatic pain and its response to treatment?
Assessment of pain in CP follows the guidelines for other types of chronic pain, where the multidimensional
nature of symptom presentation is taken into consideration. Only a few instruments have been validated for
subjective pain assessment in CP; however, several appropriate measures exist despite not being rigorously
validated in this population. (Quality assessment: moderate; Recommendation: strong; Agreement: strong)
7
ACCEPTED MANUSCRIPT
Subjective Verbal Reports
One-dimensional scales (usually pain intensity)
One-dimension scales assess a single element of pain, and allow for a simple and fast method for patients to
self-report the subjectively experienced intensity of their pain, but can oversimplify the pain
experience(27).These scales use numeric (often 0-10), verbal or visual descriptors to quantify pain or the
PT
degree of pain relief. Numerical scales, such as the visual analogue scale (VAS), are commonly applied to
RI
assess the intensity of pain in CP patients, but should be combined with a standardized registration of the
pain pattern in time(10).
SC
Multidimensional scales
Multidimensional scales measure several of the above overviewed aspects of pain, including its intensity,
U
nature and location, and in some cases, pains impact on mood or activity level. A commonly used measure
AN
in CP, the Izbicki pain score was developed to capture some of the aforementioned dimensions of pain and
provide a surrogate score(28). It has, however, never been strictly validated in patients with CP. The Brief
M
Pain Inventory (BPI) is commonly used with chronic pain patients and validated in CP. It quantifies intensity
as well as pains interference in mood, ability to work etc., and correlates with quality of life in CP
D
patients(11). The McGill Pain Questionnaire is another commonly used survey that assesses three aspects of
TE
the pain experience, including sensory, affective, and evaluative dimensions and likely a more appropriate
pain assessment measure in CP patients than unidimensional numeric scales alone(29).

EP
Quantitative Sensory Testing (QST)

C
Pain sensitivity can be reliably assessed and quantified in the laboratory using quantitative sensory testing
AC
(QST)(30). These calibrated and standardized methods for delivering noxious stimuli under controlled
conditions(31) are reflective of clinical conditions, as subjects who rate QST stimuli as most painful(32,33),
or show heightened central sensitization(34,35) report the most frequent, disabling clinical pain. Dynamic
QST techniques have the potential to more directly assess CNS pain-modulatory processes(36). QST is
frequently employed to evaluate treatment responses among CP patients. For example, pregabalin inhibited
8
ACCEPTED MANUSCRIPT
central sensitization(37), and oxycodone was found to be more effective than morphine on visceral pain in
patients with CP(38).
Q4. What is the role of smoking and alcohol on pain treatment in CP
Abstinence from alcohol and smoking, in addition to adequate treatment, should be strongly advised in
PT
patients with CP (Quality assessment: moderate (alcohol) to weak (smoking); Recommendation: strong;
RI
Agreement: strong)
SC
Alcohol: High alcohol intake is a risk factor for acute and chronic pancreatitis(39), and abstinence from
alcohol is associated with reduction in frequency of recurrence of pancreatitis(40,41). Pharmacological
U
treatment is often necessary to ensure that the patients refrain from alcohol intake. Benzodiazepines and
AN
mood stabilizers such as carbamazepine are safe and efficacious in treating moderate symptoms of alcohol
withdrawal(42). Only three medications are used for treatment of alcohol dependence; naltrexone,
M
acamprosate and disulfiram. Naltrexone has strong support in reducing relapse in alcoholics(43), while
acamprosate has shown efficacy in some(44) but not all trials(45). While disulfiram has been widely used,
D
there is no clear clinical trial data supporting positive outcomes(46).

TE
Non-pharmacological treatments have also been widely used. Several psychosocial interventions have
shown significant behavioral change in patients with alcohol dependence including cognitive behavioral
EP
therapy(47,48). Self-help organizations such as Alcoholics Anonymous can also be helpful (49).
C
Tobacco: Several studies have shown that smoking tobacco, particularly cigarettes increased the risk for
AC
developing both acute(50,51) and chronic pancreatitis(52,53) and this relative risk is dose-dependent. More
than 80% of patients with alcoholic chronic pancreatitis are smokers and smoking potentiates alcohol
toxicity in dose-dependent way(53). While cigarette smoking is often present in alcohol abuse, studies
showing smoking as an independent predictive factor are emerging(50,54). However, no study has evaluated
the effect of smoking cessation on pain in patients with CP.
9
ACCEPTED MANUSCRIPT
Pharmacological treatment: Logically, smoking cessation should be a strong recommendation. In a recent
Cochrane review nicotine replacement, bupropion, varenicline, and cytisine, another partial nicotine receptor
agonist, had the greatest evidence for improving the chances of quitting(55).
Non-pharmacological treatment: Cognitive behavioral therapy combined with smoking cessation
medications can be effective in smokers who are motivated to quit(56). Mindfulness-based therapy may also
PT
help with recovery from smoking relapse(57).
RI
Q5. Do enzymes and antioxidants influence pain in CP?
SC
Pancreatic enzyme therapy with high protease content may be tried as an initial treatment for pain relief in
patients with CP. Furthermore; combination of antioxidants in sufficient dosages should be included in the
U
armamentarium of pain treatments (Quality assessment: moderate; Recommendation: strong; Agreement:
AN
weak)
M
The pathophysiological basis of using pancreatic enzymes for pain in CP is related to the hypothesis that
nutrients stimulate the release of cholecystokinin releasing factor (CRF) from the duodenum(58). The CRF
D
then releases cholecystokinin, which stimulates pancreatic secretion and this may increase intraductal
TE
pressure in patients who have ductal obstruction. Theoretically, the pancreatic enzymes degrade CRF thus
limiting the release of cholecystokinin and subsequently decrease pancreatic secretion. Six randomized
EP
clinical trials have been reported on the effect of pancreatic enzymes in pain relief. In a review of these(59),
pain relief using pancreatic enzymes as tablets was noted in two trials(60,61) and no benefit was noted in 4
C
trials that used acid-protected capsule form of enzymes(6265). The reason could be that pancreatic enzymes
AC
were not released in the duodenum in the acid-protected form. If enzyme therapy is tried for pain relief, the
preparations should be uncoated, contain large amounts of proteases (>25,000 USP units per tablet) and be
given in a dosage of four to eight tablets four times a day.
Antioxidants may also be helpful in pain treatment. Oxidative stress as a mechanism of inflammation in CP
has been shown for the past 30 years(6670). Consequently, antioxidant supplementation has been used to
10
ACCEPTED MANUSCRIPT
ameliorate oxidative stress and relieve pain in patients with CP. Recent meta-analyses of randomized
controlled trials have shown beneficial effect of antioxidants in patients with CP(7173). A combination
of antioxidants (-carotene, vitamin C, vitamin E, selenium, and methionine) has shown significant pain
relief while studies with single antioxidant therapy showed no significant pain relief. A recent study has
shown that a combination of pregabalin and antioxidants resulted in benefit in those who had recurrence
PT
of pain after surgical and/or endoscopic therapy(74).
RI
Q6. Which analgesics are recommended for pain in chronic pancreatitis?
SC
Currently the standard guideline for analgesic therapy in CP follows the principles of the pain relief
ladder provided by the World Health Organization (WHO) adjusted to the pain characteristics of this
U
condition (Quality assessment: moderate; Recommendation: strong; Agreement: strong)
AN
The standard guidelines for analgesic therapy in CP follow the principles of the pain relief ladder provided
M
by the World Health Organization (WHO). This approach enables a simple stepwise escalation of drugs with
increasing analgesic potency (level I-III) until pain relief is obtained, with simultaneous monitoring and
D
handling of side effects (75).

TE
Simple analgesics are used as a cornerstone in pain treatment and paracetamol is the preferred level I drug
EP
due to its limited side effects. The non-steroidal anti-inflammatory drugs (NSAIDs) should in general be
avoided due to their gastrointestinal toxicity (76). This may especially be relevant in CP as patients are
C
already predisposed to peptic ulcers(77).

AC
Adjuvant analgesics are a heterogeneous group of drugs initially developed for indications other than pain
and include antidepressants, anticonvulsants as well as anxiolytics (and spasmolytics in the gut). Although
adjuvant analgesics have been widely used in the clinic to treat pain in CP, only pregabalin has been
investigated in this patient group and was found to induce a moderate pain relief (78).
11
ACCEPTED MANUSCRIPT
Anti-depressive drugs are widely used pain treatment in functional visceral pain disorders and although no
data exist in CP, their positive effects in patients with neuropathic pain (thought to be prevalent in CP)
makes them attractive(79). It is, however, unclear if their effect is mediated through direct analgesic effects
or indirectly by reducing anxiety and depression(80).
PT
Opioid analgesics seem to be a necessary step to dampen pain in many patients with CP, and it is mandatory
RI
that pancreatologists understand the complexity of opioids(81). Opioid based treatments are often associated
with many severe adverse effects such as constipation or opioid induced hyperalgesia (82,83). Patients on
SC
long-term opioid therapy must be kept under close clinical surveillance and it shall be stressed that only
about 25% of patients benefit from treatment. Some drugs such as tramadol possesses both a weak opioid
U
agonist activity along with an effect on noradrenaline and serotonin uptake(84). Tramadol is often the
AN
preferred level II analgesia and was shown to be superior to morphine in patients with CP, with fewer
gastrointestinal side effects for the same level of analgesia (85). Transdermal administration of opioids
M
should be reserved to patients having trouble with tablet ingestion. There is marked inter-individual
variability in responsiveness to different opioids, and often a trial of an alternative opioid is indicated(81,86).
D
TE
In some patients unconventional treatment with drugs such as ketamine is beneficial, but only in the hands of
pain specialists. Somastotatin-analogue inhibits pancreatic secretion and may theoretically alleviate pain
EP
through reduction of pancreatic ductal pressure. However, there are conflicting data about the efficacy. Other
drugs including clonidine, benzodiazepines, anti-psychotics or cannabinoids may also be beneficial in

C
difficult cases.
AC
Figure 1
In clinical practice pain treatment is mainly guided by evidence from somatic pain studies together with
individual experience and traditions. In figure 1 the pain treatment algorithm used at Centre for Pancreatic
Diseases, Aalborg University Hospital, Denmark is shown. This includes neurophysiological and
12
ACCEPTED MANUSCRIPT
psychological testing. For example segmental hyperalgesia of the epigastric skin area (pancreatic
viscerotome) may predict the response to gabapentinoids(87).
Q7. Is endoscopical therapy effective for pain treatment in CP?
The best candidates for successful treatment of painful CP with first-line endoscopical therapy are patients
PT
with distal obstruction of the main pancreatic duct (single stone and/or single stricture in the head of the
RI
pancreas) and in the early stage of the disease. Endoscopical therapy can be combined with Extracorporeal
Shock Wave Lithotripsy (ESWL) in the presence of large (> 4 mm) obstructive stone(s) located in the
SC
pancreatic head, and with ductal stenting in the presence of a dominant main pancreatic duct stricture that
induces a markedly dilated duct. (Quality assessment: moderate; Recommendation: strong; Agreement:
U
conditional)
AN
Endoscopical therapy (ET) in painful CP is based on the rationale that pain is related to an outflow
M
obstruction of the main pancreatic duct (MPD) due to stricture(s) or pancreatic intraductal stone(s).
Endoscopic retrograde cholangio-pancreatography (ERCP) can achieve MPD drainage by sphincterotomy of

D
the major and/or minor papilla, by short-term stent placement or by pancreatic stone extraction, usually after
TE
fragmentation with ESWL.

EP
The effectiveness of ET is usually the result of these combined procedures; all of these are aimed to restore
drainage of the MPD. With this approach about 60% experience complete or partial pain relief both in the
C
short (< 2 years) and long-term follow-up (> 5 years). However, the quality of evidence of reported results
AC
remains low in most of these retrospective observational non-randomized studies (see Tables and studies in
Appendix). Only two randomized controlled trial (RCT) compared ET and surgery, and both favored
surgery(88,89). There were, however, several shortcomings. Among them was the low technical success rate
(88) and suboptimal procedures (89) compared with previous studies (Tables in Appendix). Contrary to
surgery, ET is possible in patients with risk factors such as older age and co-morbidities. Factors predicting
favorable clinical outcome after ET ESWL have been identified and are shown in figure 2(90,91) (see also
13
ACCEPTED MANUSCRIPT
Tables in Appendix), and if clinical success can be obtained with 5 endoscopic interventions, the patient
will probably achieve long-term favorable outcome.
Figure 2
PT
Q8. Is ESWL effective for pain treatment in CP?
RI
In patients with uncomplicated painful calcified CP, ESWL alone is a safe and effective treatment. Best
candidates for benefiting from initial first-line ESWL are patients with obstructive calcifications, > 4 mm
SC
confined to the head of pancreas. Combining systematic endoscopical therapy with ESWL adds to the cost of
patient care, at the same time not probably improving the outcome of pancreatic pain (Quality assessment:
U
moderate, Recommendation strong; Agreement: conditional).
AN
ESWL for pancreatic stones is indicated for patients with all of the following:
M
1. recurrent attacks of pancreatic pain
2. moderate to marked changes in the pancreatic ductal system

D
3. obstructing ductal stones (minimal diameter: 2 5 mm, calcified or radiolucent)(92)

TE
Regardless of the method of shock waves generation ESWL provides high rates of stones fragmentation
(average of 91% ranging from 54 to 100%)(92). ESWL was proven useful for treating CP related pain in
EP
several meta-analyses(93)(94) where the pooled proportion of patients with absence of pain at FU was about
50% and narcotic use was decreased in 80%. In a prospective randomized study that compared ESWL alone
C
with ESWL combined with endoscopy(95), there was no evidence that the combination of endoscopy and
AC
ESWL was better than ESWL alone for pain treatment. Data regarding duct clearance have been somewhat
conflicting ranging between similar for the procedures alone(96) to a better outcome for the combined
procedures(97). Factors associated with complete stone clearance included the presence of a single stone vs.
multiple stones(98,99), the absence of a MPD stricture(98) and a lower density of stones (< 820 Hounsfield
units)(100).
14
ACCEPTED MANUSCRIPT
After treatment with ESWL (alone or combined with endoscopic drainage), most of the patients who
experienced pain relapses developed them during the first two years following treatment(90,95,101). Pain
relapse occurred significantly more frequently in patients with incomplete removal of stones after the initial
therapy and in those with a MPD stricture(98). Other factors associated with long-term pain relief are short
PT
disease duration, low frequency of pain attacks before treatment, complete ductal stone clearance, absence of
RI
MPD stricture and discontinuation of alcohol and tobacco (90,98,101,102).
SC
Q9. Are other treatments (neurolytical, psychological, etc.) effective for pain management in CP?
Neurolytical interventions can be used in selected patients with painful CP who have failed endoscopic and
U
surgical treatment. Thoracoscopic splanchnic denervation is more effective regarding long-term pain relief
AN
in patients who are not on chronic opioid treatment. Behavioral interventions should be part of the
multidisciplinary approach in CP pain particularly when patients experience psychological impact of pain
M
and quality of life has decreased. Early intervention in children may be particularly important. (Quality
assessment: low; Recommendation: strong; Agreement: conditional)

D
TE
Neurolytic interventions: Celiac plexus blocks and splanchnic nerve ablation of patients with CP are
EP
generally advised when other medical treatments for pain have failed. Several techniques for percutaneous
celiac plexus blockade have been described(103), but pain relief only lasts for short term with a risk for side
C
effects such as postural hypotension and diarrhea. Therefore celiac plexus block is nowadays rarely applied
AC
in CP. Thoracoscopic splanchnicectomy was first described as a minimally invasive therapy for pain in
1994(104); however, to date no RCT has been done. Preoperative opioid use, duration of disease and pain
seem to impair long term results probably due to central sensitization(105)
There are only a few studies of spinal cord stimulation and transcranial magnetic stimulation in chronic
pancreatitis(106,107). Pain relief by spinal cord stimulation was achieved in 66 % of patients, but a
15
ACCEPTED MANUSCRIPT
drawback of the procedure is its invasiveness. Repetitive TMS holds promise for treating depression in
chronic pancreatitis patients with a possible concurrent pain relieving effect.
Psychological/psychiatric interventions: There is a paucity of studies in CP, but in other chronic pain
conditions psychological interventions have been shown to be efficacious (108,109). Interventions include
PT
cognitive behavioral therapy, mindfulness approaches, hypnosis etc.(110113).
RI
Children with CP represent an important subgroup who experiences frequent pancreatitis-related abdominal
pain(114), but there are no studies conducted to date. However, psychological treatments for other forms of
SC
pediatric chronic pain have promising effects.
U
Q10. What is the optimal surgical approach to relieve pain in CP?
AN
Depending on the morphological changes of the pancreas and pain processing status a (partially) resection,
decompression of the pancreatic duct or combined interventions can be performed to reduce pain. Long-
M
term effects are variable, but success rates up to 80% have been reported. The emerging role of total
pancreatectomy as initial surgical treatment looks promising but needs further investigation (Quality
D
assessment: moderate; Recommendation: strong; Agreement: conditional)

TE
Surgical options for pain are classified into three categories: a) decompression (focusing on ductal
EP
hypertension), b) resection (focusing on inflammatory masses and stones in the pancreatic head) and c)
combined procedures. Although long-term results of surgery are promising, most of studies to date are
C
observational or only compare different invasive procedures. There are several procedures available
AC
dependent of the indication (see Appendix). In randomized controlled trials, tailored organ-sparing
procedures have been found to be superior to Whipple or the pylorus-preserving Whipple procedure in
regard to pain relief (75%) and morbidity (20%)(115,116). An indication for total pancreatectomy
(with/without islet autotransplantation) is to palliate pain especially before diabetes mellitus has developed
(117,118). When central sensitization is present endoscopic and/or surgical therapy has a higher risk of
failure. Factors that are relevant in developing sensitization are duration of the disease, age, pain history and
16
ACCEPTED MANUSCRIPT
previous invasive treatment(119). Surgery has to be tailored to the needs of patients and should be organ
sparing in a high-volume center with expertise in pancreatic surgery.
Q11. When is the optimal time for surgery in painful CP?
Current evidence on the timing of surgery for painful CP suggests a beneficial role for early surgery, i.e. 1)
PT
within the first 2 to 3 years after diagnosis or symptom onset, 2) for patients who had equal to or fewer than
RI
5 endoscopic procedures, and 3) for patients who have not yet required opioid analgesics for medical pain
treatment (Quality assessment: low; Recommendation: weak; Agreement: strong).
SC
Although there are no prospective controlled studies that specifically addressed the timing of surgery for
U
painful CP, increasing amount of evidence suggests that surgery should be considered early for better pain
AN
outcomes. In a systematic review that analyzed the role of timing, it was found that early surgery was
associated with a greater probability to attain postoperative pain relief (120). The optimal cutoff point for
M
was found 26.5 months or less(121). Preoperative opioid use and 5 or more endoscopic interventions also
seems to have negative influence(122,123). In patients with obstruction of the duct system timing can be
D
decisive for the outcome.

TE
Q 12. How to manage pain "relapse" after surgery or endoscopy for painful CP?
EP
Current evidence suggests that the first step for the management of pain relapse should be exclusion of
obstructing stones or strictured anastomosis via imaging, followed by a limited number endoscopic
C
interventions, and early consideration of re-surgery to achieve pain control (Quality assessment: weak;
AC
Recommendation: strong; Agreement: weak).
After both surgery(124126) and endoscopy(127), the long-term (5-year) pain free status is around 50 to
60%. Patients with pain relapse after endoscopical treatment may benefit of combined antioxidant-pregabalin
therapy(74). There is lack of sufficient evidence for concrete recommendations for managing pain relapse
after surgery, but surgeons should consider that any kind of subsequent treatment may be subject to failure
17
ACCEPTED MANUSCRIPT
due to irreversible neuropathic alterations (79,128). In all cases, it is crucial to first exclude more simple
reasons for therapy failure such as obvious stricture of anastomosis, or obstructing stones in the pancreatic or
bile duct(129). Furthermore, it should be considered that a salvage operation for pain relapse may end up in a
total pancreatectomy
PT
RI
Q13. What are the indications for referral to a specialist center for further investigation of pain?
All patients with presumed or established diagnosis of CP should be routinely referred to specialist
SC
pancreatic centers for investigation and treatment of their disease (Quality assessment: moderate;
Recommendation: strong; Agreement: strong).
U
AN
Referral should be considered when non-specialist management is failing, chronic pain is poorly controlled,
there is significant distress, and/or where specific specialist intervention or assessment is considered. A
M
systematic review of observational studies (although not in CP) concluded that a longer delay between
specialist referral and specialist consultation resulted in poorer health and pain management(130).
D
TE
C EP
AC
18
ACCEPTED MANUSCRIPT
Figure legends
Figure 1. Suggested algorithm for pharmacological treatment (grey boxes) of pain in chronic
pancreatitis. In most cases, combination therapies are necessary. Treatment with antidepressives is
PT
guided by psychological evaluation including assessment of catastrophizing, depression etc. In case
gabapentinoids are considered we use evaluation of the ration between segmental and generalised
RI
hyperalgesia (see text). Of note, treatment with gabapentinoids, TCA, SNRI (or SSRI in selected
SC
cases) should be titrated slowly until sufficient effect or intolerable adverse effects occur. Treatment
shall be individualised due to major differences in receptor properties and analgesic mechanisms
U
between patients. Non-steroidal anti-inflammatory drugs (NSAIDs) are normally not indicated and
AN
should be used carefully. Opioids shall be avoided if possible due to the major side effects on the
gastrointestinal tract etc., but in severe pain they may be prescribed for limited periods and the
M
physician shall always be aware of opioid induced bowel dysfunction and hyperalgesia (narcotic
D
bowel).
Plus sign indicate sufficient/satisfactory effect.

TE
Minus sign indicate insufficient effect

EP
ESWL: extracorporal shock wave lithotrypsy
PCM: paracetamol
C
NSAID: non-steroidal anti-inflammatory drugs

AC
TCA: tricyclic antidepressives
SNRI: serotonin-noradrenalin reuptake inhibitors
SSRI: selective serotonin reuptake inhibitors
OIBD: opioid induced bowel dysfunction
19
ACCEPTED MANUSCRIPT
Figure 2: The first step for the management of pain in patients with chronic pancreatitis should be to
make a correct diagnosis based on clinical history and imaging procedures, and to exclude
alternative diseases or complications that could induce pain not related to pancreatic ductal
PT
obstruction by stones and/or strictures.
The second step should be to select the appropriate candidates for endoscopy (see the text for the
RI
definition of best candidates for endoscopical treatment with or without ESWL) and to treat such
SC
good candidates early in the disease course (within the first 2 to 3 years after symptom onset), with
a limited number (< or = 5) of endoscopic interventions. If no persistent pain relief was obtained
U
after a limited trial of endoscopic treatments +/- ESWL, that means that other factors than increased
AN
pancreatic ductal pressure could be involved in the pain syndrome and for these patients no further
attempts at drainage should be proposed. In these patients or if the patient is not a candidate for
M
endoscopy or in case of technical failure of endoscopy, medical treatment could be tried. Surgery
D
and alternative options could also be proposed if no persistent pain relief was obtained after
endoscopy, in case of limited effect of medical treatment.

TE
C EP
AC
20
ACCEPTED MANUSCRIPT
References
1. Lhr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, Lerch MM, et al.
United European Gastroenterology evidence-based guidelines for the diagnosis and therapy
of chronic pancreatitis (HaPanEU). United Eur Gastroenterol J [Internet]. SAGE
PT
PublicationsSage UK: London, England; 2017 Mar [cited 2017 Mar 16];5(2):15399.
Available from: http://journals.sagepub.com/doi/10.1177/2050640616684695
RI
2. Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic
SC
pancreatitis: An international draft consensus proposal for a new mechanistic definition.
Pancreatology [Internet]. 2016 Mar [cited 2017 Mar 16];16(2):21824. Available from:
U
http://linkinghub.elsevier.com/retrieve/pii/S1424390316000405
AN
3. Yadav D, Lowenfels AB. The Epidemiology of Pancreatitis and Pancreatic Cancer.
Gastroenterology [Internet]. 2013 May [cited 2017 Mar 7];144(6):125261. Available from:
M
http://www.ncbi.nlm.nih.gov/pubmed/23622135
D
4. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses
of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology

TE
[Internet]. 1994 Nov [cited 2017 Mar 7];107(5):14817. Available from:

EP
5. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic

C
pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients.

AC
Gastroenterology [Internet]. 1984 May [cited 2017 Mar 7];86(5 Pt 1):8208. Available from:
6. Cavallini G, Frulloni L, Pederzoli P, Talamini G, Bovo P, Bassi C, et al. Long-term follow-
up of patients with chronic pancreatitis in Italy. Scand J Gastroenterol [Internet]. 1998 Aug
[cited 2017 Mar 7];33(8):8809. Available from:
21
ACCEPTED MANUSCRIPT
7. Lankisch PG, Lhr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis.
Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion
[Internet]. 1993 [cited 2017 Mar 7];54(3):14855. Available from:
PT
8. Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis.
RI
Gastroenterology [Internet]. 1999 May [cited 2017 Mar 7];116(5):113240. Available from:
SC
9. Lankisch PG, Seidensticker F, Lhr-Happe A, Otto J, Creutzfeldt W. The course of pain is
U
the same in alcohol- and nonalcohol-induced chronic pancreatitis. Pancreas [Internet]. 1995
AN
May [cited 2017 Mar 7];10(4):33841. Available from:
M
10. Mullady DK, Yadav D, Amann ST, OConnell MR, Barmada MM, Elta GH, et al. Type of
D
pain, pain-associated complications, quality of life, disability and resource utilisation in
chronic pancreatitis: a prospective cohort study. Gut [Internet]. 2011 Jan 1 [cited 2017 Mar
TE
8];60(1):7784. Available from: http://gut.bmj.com/cgi/doi/10.1136/gut.2010.213835

EP
11. Olesen SS, Juel J, Nielsen AK, Frkjr JB, Wilder-Smith OHG, Drewes AM. Pain severity
reduces life quality in chronic pancreatitis: Implications for design of future outcome trials.
C
Pancreatology [Internet]. 2014 Nov [cited 2017 Mar 8];14(6):497502. Available from:
AC
12. Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, et al. The
neurotrophic factor artemin influences the extent of neural damage and growth in chronic
pancreatitis. Gut [Internet]. 2007 Apr 1 [cited 2017 Mar 7];56(4):53444. Available from:
http://gut.bmj.com/cgi/doi/10.1136/gut.2006.105528
22
ACCEPTED MANUSCRIPT
13. Abu Dayyeh BK, Conwell D, Buttar NS, Kadilaya V, Hart PA, Baumann NA, et al.
Pancreatic juice prostaglandin e2 concentrations are elevated in chronic pancreatitis and
improve detection of early disease. Clin Transl Gastroenterol [Internet]. 2015 Jan 29 [cited
2017 Mar 7];6(1):e72. Available from:
PT
http://www.nature.com/doifinder/10.1038/ctg.2014.23
14. Pasricha PJ. Unraveling the mystery of pain in chronic pancreatitis. Nat Rev Gastroenterol
RI
Hepatol [Internet]. 2012 Jan 24 [cited 2017 Mar 13];9(3):14051. Available from:
SC
http://www.nature.com/doifinder/10.1038/nrgastro.2011.274
15. Wilcox CM, Yadav D, Ye T, Gardner TB, Gelrud A, Sandhu BS, et al. Chronic pancreatitis
U
pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol
AN
Hepatol [Internet]. 2015 Mar [cited 2017 Mar 7];13(3):552-60-9. Available from:
M
16. Feng QX, Wang W, Feng XY, Mei XP, Zhu C, Liu ZC, et al. Astrocytic activation in
D
thoracic spinal cord contributes to persistent pain in rat model of chronic pancreatitis.
Neuroscience [Internet]. 2010 May 5 [cited 2017 Mar 7];167(2):5019. Available from:
TE
EP
17. Liu P-Y, Lu C-L, Wang C-C, Lee I-H, Hsieh J-C, Chen C-C, et al. Spinal microglia initiate
and maintain hyperalgesia in a rat model of chronic pancreatitis. Gastroenterology [Internet].

C
2012 Jan [cited 2017 Mar 7];142(1):165173.e2. Available from:

AC
18. Vera-Portocarrero LP, Xie JY, Yie JX, Kowal J, Ossipov MH, King T, et al. Descending
facilitation from the rostral ventromedial medulla maintains visceral pain in rats with
experimental pancreatitis. Gastroenterology [Internet]. 2006 Jun [cited 2017 Mar
7];130(7):215564. Available from:
23
ACCEPTED MANUSCRIPT
19. Bouwense SAW, Olesen SS, Drewes AM, Frkjr JB, van Goor H, Wilder-Smith OHG. Is
altered central pain processing related to disease stage in chronic pancreatitis patients with
pain? An exploratory study. Milanese S, editor. PLoS One [Internet]. 2013 Feb 6 [cited 2017
PT
Mar 7];8(2):e55460. Available from: http://dx.plos.org/10.1371/journal.pone.0055460
20. Dimcevski G, Sami SAK, FunchJensen P, Le Pera D, Valeriani M, ArendtNielsen L, et al.
RI
Pain in Chronic Pancreatitis: The Role of Reorganization in the Central Nervous System.
SC
Gastroenterology [Internet]. 2007 Apr [cited 2017 Mar 13];132(4):154656. Available from:
U
21. Buscher HCJL, Wilder-Smith OHG, van Goor H. Chronic pancreatitis patients show
AN
hyperalgesia of central origin: a pilot study. Eur J Pain [Internet]. 2006 May [cited 2017 Mar
7];10(4):36370. Available from: http://doi.wiley.com/10.1016/j.ejpain.2005.06.006

M
22. Olesen SS, Brock C, Krarup AL, Funch-Jensen P, Arendt-Nielsen L, Wilder-Smith OH, et al.
D
Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis. Clin
Gastroenterol Hepatol [Internet]. 2010 Aug [cited 2017 Mar 7];8(8):72430. Available from:
TE
EP
23. Olesen SS, Frkjr JB, Lelic D, Valeriani M, Drewes AM. Pain-associated adaptive cortical
reorganisation in chronic pancreatitis. Pancreatology [Internet]. 2010 Mar [cited 2017 Mar
C
7];10(6):74251. Available from:

AC
24. Olesen SS, Hansen TM, Graversen C, Steimle K, Wilder-Smith OHG, Drewes AM. Slowed
EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain
processing? Eur J Gastroenterol Hepatol [Internet]. 2011 May [cited 2017 Mar 7];23(5):418
24. Available from:
24
ACCEPTED MANUSCRIPT
http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00042737-
201105000-00008
25. de Vries M, Wilder-Smith OH, Jongsma M LA, van den Broeke EN, Arns M, van Goor H, et
al. Altered resting state EEG in chronic pancreatitis patients: toward a marker for chronic
PT
pain. J Pain Res [Internet]. 2013 Nov 25 [cited 2017 Mar 7];6:81524. Available from:
http://www.dovepress.com/altered-resting-state-eeg-in-chronic-pancreatitis-patients-toward-
RI
a-ma-peer-reviewed-article-JPR
SC
26. Uc A, Andersen DK, Bellin MD, Bruce JI, Drewes AM, Engelhardt JF, et al. Chronic
Pancreatitis in the 21st Century - Research Challenges and Opportunities: Summary of a
U
National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas
AN
M
27. Marco CA, Nagel J, Klink E, Baehren D. Factors associated with self-reported pain scores
D
among ED patients. Am J Emerg Med [Internet]. 2012 Feb [cited 2017 Mar 7];30(2):3317.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/21367555

TE
28. Bloechle C, Izbicki JR, Knoefel WT, Kuechler T, Broelsch CE. Quality of life in chronic
EP
pancreatitis--results after duodenum-preserving resection of the head of the pancreas.
Pancreas [Internet]. 1995 Jul [cited 2017 Mar 7];11(1):7785. Available from:
C
AC
29. Seicean A, Grigorescu M, Tanu M, Dumitracu DL, Pop D, Mocan T. Pain in chronic
pancreatitis: assessment and relief through treatment. Rom J Gastroenterol [Internet]. 2004
Mar [cited 2017 Mar 7];13(1):915. Available from:
30. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain
25
ACCEPTED MANUSCRIPT
[Internet]. 2011 Mar [cited 2017 Mar 7];152(Supplement):S215. Available from:
31. Gracely RH. Pain measurement. Acta Anaesthesiol Scand [Internet]. 1999 Oct [cited 2017
Mar 7];43(9):897908. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10522737
PT
32. Edwards RR, Fillingim RB. Ethnic differences in thermal pain responses. Psychosom Med
[Internet]. [cited 2017 Mar 7];61(3):34654. Available from:
RI
SC
33. Fillingim RB, Edwards RR, Powell T. The relationship of sex and clinical pain to
experimental pain responses. Pain [Internet]. 1999 Dec [cited 2017 Mar 7];83(3):41925.
U
AN
34. Edwards RR, Fillingim RB. Effects of age on temporal summation and habituation of
thermal pain: clinical relevance in healthy older and younger adults. J Pain [Internet]. 2001
M
Dec [cited 2017 Mar 7];2(6):30717. Available from:

D
35. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious
TE
inhibitory controls (DNIC): association with clinical variables. Pain [Internet]. 2003 Dec
EP
C
36. Granovsky Y, Yarnitsky D. Personalized pain medicine: the clinical value of psychophysical
AC
assessment of pain modulation profile. Rambam Maimonides Med J [Internet]. 2013 Oct 29
[cited 2017 Mar 7];4(4):e0024. Available from:
http://www.rmmj.org.il/(S(sef2mr2er5p4lsb3kefhcwa0))/Pages/Article.aspx?manuId=336
37. Bouwense SAW, Olesen SS, Drewes AM, Poley J-W, van Goor H, Wilder-Smith OHG.
Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a
26
ACCEPTED MANUSCRIPT
randomized, controlled trial. Eldabe S, editor. PLoS One [Internet]. 2012 Aug 6 [cited 2017
38. Staahl C, Dimcevski G, Andersen SD, Thorsgaard N, Christrup LL, Arendt-Nielsen L, et al.
Differential effect of opioids in patients with chronic pancreatitis: an experimental pain
PT
study. Scand J Gastroenterol [Internet]. 2007 Mar 8 [cited 2017 Mar 7];42(3):38390.
Available from: http://www.tandfonline.com/doi/full/10.1080/00365520601014414
RI
39. Samokhvalov A V, Rehm J, Roerecke M. Alcohol Consumption as a Risk Factor for Acute
SC
and Chronic Pancreatitis: A Systematic Review and a Series of Meta-analyses.
EBioMedicine [Internet]. 2015 Dec [cited 2017 Mar 7];2(12):19962002. Available from:
U
AN
40. Pelli H, Lappalainen-Lehto R, Piironen A, Sand J, Nordback I. Risk factors for recurrent
acute alcohol-associated pancreatitis: A prospective analysis. Scand J Gastroenterol

M
[Internet]. 2008 Jan 8 [cited 2017 Mar 7];43(5):61421. Available from:

D
41. Nikkola J, Rty S, Laukkarinen J, Seppnen H, Lappalainen-Lehto R, Jrvinen S, et al.

TE
Abstinence after first acute alcohol-associated pancreatitis protects against recurrent

EP
pancreatitis and minimizes the risk of pancreatic dysfunction. Alcohol Alcohol [Internet].
2013 Jul 1 [cited 2017 Mar 7];48(4):4836. Available from:

C
https://academic.oup.com/alcalc/article-lookup/doi/10.1093/alcalc/agt019
AC
42. Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal
syndrome. J Clin Pharm Ther [Internet]. 2010 Apr [cited 2017 Mar 7];35(2):15367.
Available from: http://doi.wiley.com/10.1111/j.1365-2710.2009.01098.x
43. Volpicelli JR, Alterman AI, Hayashida M, OBrien CP. Naltrexone in the treatment of
alcohol dependence. Arch Gen Psychiatry [Internet]. 1992 Nov [cited 2017 Mar
27
ACCEPTED MANUSCRIPT
7];49(11):87680. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1345133
44. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy
for Adults With Alcohol Use Disorders in Outpatient Settings. Jama [Internet].
2014;311(7110):1889. Available from:
PT
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.3628%5Cnhttp://jama.ja
manetwork.com/article.aspx?articleid=1869208
RI
45. Anton RF, OMalley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. Combined
SC
pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE
study: a randomized controlled trial. JAMA [Internet]. 2006 May 3 [cited 2017 Mar
U
7];295(17):200317. Available from:
AN
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.295.17.2003
46. Mutschler J, Grosshans M, Soyka M, Rsner S. Current Findings and Mechanisms of Action
M
of Disulfiram in the Treatment of Alcohol Dependence. Pharmacopsychiatry [Internet]. 2016

D
Jul 17 [cited 2017 Mar 7];49(4):13741. Available from: http://www.thieme-
connect.de/DOI/DOI?10.1055/s-0042-103592
TE
47. Starosta AN, Leeman RF, Volpicelli JR. The BRENDA model: integrating psychosocial
EP
treatment and pharmacotherapy for the treatment of alcohol use disorders. J Psychiatr Pract
[Internet]. 2006 Mar [cited 2017 Mar 7];12(2):809. Available from:

C
AC
48. Magill M, Kiluk BD, McCrady BS, Tonigan JS, Longabaugh R. Active Ingredients of
Treatment and Client Mechanisms of Change in Behavioral Treatments for Alcohol Use
Disorders: Progress 10 Years Later. Alcohol Clin Exp Res [Internet]. 2015 Oct [cited 2017
Mar 7];39(10):185262. Available from: http://doi.wiley.com/10.1111/acer.12848
49. Ferri M, Amato L, Davoli M. Alcoholics Anonymous and other 12-step programmes for
28
ACCEPTED MANUSCRIPT
alcohol dependence. Ferri M, editor. Cochrane database Syst Rev [Internet]. Chichester, UK:
John Wiley & Sons, Ltd; 2006 Jul 19 [cited 2017 Mar 7];(3):CD005032. Available from:
http://doi.wiley.com/10.1002/14651858.CD005032.pub2
50. Yuhara H, Ogawa M, Kawaguchi Y, Igarashi M, Mine T. Smoking and risk for acute
PT
pancreatitis: a systematic review and meta-analysis. Pancreas [Internet]. 2014 Nov [cited
2017 Mar 7];43(8):12017. Available from:
RI
SC
201411000-00012
51. Sun X, Huang X, Zhao R, Chen B, Xie Q. Meta-analysis: Tobacco smoking may enhance the
U
risk of acute pancreatitis. Pancreatology [Internet]. 2015 May [cited 2017 Mar 7];15(3):286
AN
94. Available from: http://linkinghub.elsevier.com/retrieve/pii/S142439031500040X
52. Alexandre M, Pandol SJ, Gorelick FS, Thrower EC. The emerging role of smoking in the
M
development of pancreatitis. Pancreatology [Internet]. 2011 Jan [cited 2017 Mar

D
TE
53. Edderkaoui M, Thrower E. Smoking and Pancreatic Disease. J Cancer Ther [Internet]. 2013
EP
Nov 1 [cited 2017 Mar 7];4(10A):3440. Available from:
http://www.scirp.org/journal/PaperDownload.aspx?DOI=10.4236/jct.2013.410A005
C
54. Maisonneuve P. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis.

AC
Gut [Internet]. 2005 Apr 1 [cited 2017 Mar 7];54(4):5104. Available from:
55. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking
cessation: an overview and network meta-analysis. Cahill K, editor. Cochrane database Syst
Rev [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2013 May 31 [cited 2017 Mar
29
ACCEPTED MANUSCRIPT
7];(5):CD009329. Available from: http://doi.wiley.com/10.1002/14651858.CD009329.pub2
56. Iliceto P, Fino E, Pasquariello S, DAngelo Di Paola ME, Enea D. Predictors of success in
smoking cessation among Italian adults motivated to quit. J Subst Abuse Treat [Internet].
2013 May [cited 2017 Mar 7];44(5):53440. Available from:
PT
57. Vidrine JI, Spears CA, Heppner WL, Reitzel LR, Marcus MT, Cinciripini PM, et al. Efficacy
RI
of mindfulness-based addiction treatment (MBAT) for smoking cessation and lapse recovery:
SC
A randomized clinical trial. J Consult Clin Psychol [Internet]. 2016 Sep [cited 2017 Mar
7];84(9):82438. Available from: http://doi.apa.org/getdoi.cfm?doi=10.1037/ccp0000117
U
58. Owyang C, Louie DS, Tatum D. Feedback regulation of pancreatic enzyme secretion.
AN
Suppression of cholecystokinin release by trypsin. J Clin Invest [Internet]. 1986 Jun 1 [cited
2017 Mar 7];77(6):20427. Available from: http://www.jci.org/articles/view/112534

M
59. Warshaw AL, Banks PA, Fernndez-Del Castillo C. AGA technical review: treatment of pain
D
in chronic pancreatitis. Gastroenterology [Internet]. 1998 Sep [cited 2017 Mar

TE
60. Slaff J, Jacobson D, Tillman CR, Curington C, Toskes P. Protease-specific suppression of

EP
pancreatic exocrine secretion. Gastroenterology [Internet]. 1984 Jul [cited 2017 Mar

C
61. Braganza JM. A framework for the aetiogenesis of chronic pancreatitis. Digestion [Internet].
AC
1998 [cited 2017 Mar 7];59 Suppl 4:112. Available from:
62. Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy in
patients with chronic pancreatitis. Scand J Gastroenterol [Internet]. 1986 Jan [cited 2017 Mar
30
ACCEPTED MANUSCRIPT
63. Mssner J, Secknus R, Meyer J, Niederau C, Adler G. Treatment of pain with pancreatic
extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter trial.
Digestion [Internet]. 1992 [cited 2017 Mar 7];53(12):5466. Available from:
PT
64. Malesci A, Gaia E, Fioretta A, Bocchia P, Ciravegna G, Cantor P, et al. No effect of long-
term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic
RI
pancreatitis. Scand J Gastroenterol [Internet]. 1995 Apr [cited 2017 Mar 7];30(4):3928.
SC
65. larvin M,McMohan MJ, Thomas WEG PM. Creon (enteric coated pancreatin microspheres)
U
for the treatment of pain in chronic pancreatitis: a double-blind randomised placebo-
AN
controlled crossover study. Gastroenterology. 1991;(100):A283.
66. Szuster-Ciesielska A, Daniluk J, Kandefer-Szersze M. Oxidative stress in blood of patients

M
with alcohol-related pancreatitis. Pancreas [Internet]. 2001 Apr [cited 2017 Mar
D
67. Hausmann DH, Porstmann T, Weber I, Hausmann S, Dummler W, Liebe S, et al. Cu/Zn-
TE
SOD in human pancreatic tissue and pancreatic juice. Int J Pancreatol [Internet]. 1997 Dec
EP
C
68. Van Gossum A, Closset P, Noel E, Cremer M, Neve J. Deficiency in antioxidant factors in
AC
patients with alcohol-related chronic pancreatitis. Dig Dis Sci [Internet]. 1996 Jun [cited
2017 Mar 7];41(6):122531. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8654156
69. Braganza JM, Schofield D, Snehalatha C, Mohan V. Micronutrient antioxidant status in
tropical compared with temperate-zone chronic pancreatitis. Scand J Gastroenterol [Internet].
1993 Dec [cited 2017 Mar 7];28(12):1098104. Available from:
31
ACCEPTED MANUSCRIPT
70. Basso D, Panozzo MP, Fabris C, del Favero G, Meggiato T, Fogar P, et al. Oxygen derived
free radicals in patients with chronic pancreatic and other digestive diseases. J Clin Pathol
[Internet]. 1990 May [cited 2017 Mar 7];43(5):4035. Available from:
PT
71. Ahmed Ali U, Jens S, Busch OR, Keus F, van Goor H, Gooszen HG, et al. Antioxidants for
RI
pain in chronic pancreatitis. In: Ahmed Ali U, editor. Cochrane Database of Systematic
SC
Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2014 [cited 2017 Mar 7]. p.
CD008945. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25144441
U
72. Zhou D, Wang W, Cheng X, Wei J, Zheng S. Antioxidant therapy for patients with chronic
AN
pancreatitis: A systematic review and meta-analysis. Clin Nutr [Internet]. 2015 Aug [cited

M
D
73. Talukdar R, Murthy HV V, Reddy DN. Role of methionine containing antioxidant
combination in the management of pain in chronic pancreatitis: a systematic review and

TE
meta-analysis. Pancreatology [Internet]. 2015 Mar [cited 2017 Mar 7];15(2):13644.

EP
Available from: http://linkinghub.elsevier.com/retrieve/pii/S1424390315000150
74. Talukdar R, Lakhtakia S, Nageshwar Reddy D, Rao GV, Pradeep R, Banerjee R, et al.
C
Ameliorating effect of antioxidants and pregabalin combination in pain recurrence after

AC
ductal clearance in chronic pancreatitis: Results of a randomized, double blind, placebo-
controlled trial. J Gastroenterol Hepatol [Internet]. 2016 Sep [cited 2017 Mar
14];31(9):165462. Available from: http://doi.wiley.com/10.1111/jgh.13332
75. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping
up the quality of its evaluation. JAMA [Internet]. 1995 Dec 20 [cited 2017 Mar
32
ACCEPTED MANUSCRIPT
76. Thiagarajan P, Jankowski JA. Aspirin and NSAIDs; benefits and harms for the gut. Best
Pract {&} Res Gastroenterol. 2012 Apr;26(2):197206.
77. Poulsen JL, Olesen SS, Malver LP, Frkjr JB, Drewes AM. Pain and chronic pancreatitis: a
PT
complex interplay of multiple mechanisms. World J Gastroenterol [Internet]. 2013 Nov 14
[cited 2017 Mar 8];19(42):728291. Available from: http://www.wjgnet.com/1007-
RI
9327/full/v19/i42/7282.htm
SC
78. Olesen SS, Bouwense S a W, Wilder-Smith OHG, van Goor H, Drewes AM. Pregabalin
reduces pain in patients with chronic pancreatitis in a randomized, controlled trial.
U
Gastroenterology. Elsevier Inc.; 2011 Aug;141(2):53643.
AN
79. Drewes AM, Krarup AL, Detlefsen S, Malmstrm M-L, Dimcevski G, Funch-Jensen P. Pain
in chronic pancreatitis: the role of neuropathic pain mechanisms. Gut [Internet]. 2008 Nov 1
M

D
80. Thorkelson G, Bielefeldt K, Szigethy E. Empirically Supported Use of Psychiatric

TE
Medications in Adolescents and Adults with IBD. Inflamm Bowel Dis [Internet]. 2016 Jun
EP
C
201606000-00028
AC
81. OBrien T, Christrup LL, Drewes AM, Fallon MT, Kress HG, McQuay HJ, et al. European
Pain Federation position paper on appropriate opioid use in chronic pain management. Eur J
Pain [Internet]. 2017 Jan [cited 2017 Mar 16];21(1):319. Available from:
http://doi.wiley.com/10.1002/ejp.970
82. Drewes AM, Munkholm P, Simrn M, Breivik H, Kongsgaard UE, Hatlebakk JG, et al.
33
ACCEPTED MANUSCRIPT
Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction
Recommendations of the Nordic Working Group. Scand J Pain [Internet]. 2016 Apr [cited
2017 Mar 15];11:11122. Available from:
PT
83. Drossman D, Szigethy E. The narcotic bowel syndrome: a recent update. Am J Gastroenterol
Suppl [Internet]. 2014 Sep 10 [cited 2017 Mar 8];2(1):2230. Available from:
RI
http://www.nature.com/doifinder/10.1038/ajgsup.2014.6
SC
84. Olesen SS, Juel J, Graversen C, Kolesnikov Y, Wilder-Smith OHG, Drewes AM.
Pharmacological pain management in chronic pancreatitis. World J Gastroenterol [Internet].
U
2013 Nov 14 [cited 2017 Mar 8];19(42):7292. Available from:
AN
85. Wilder-Smith CH, Hill L, Osler W, OKeefe S. Effect of tramadol and morphine on pain and
M
gastrointestinal motor function in patients with chronic pancreatitis. Dig Dis Sci [Internet].
D
1999 Jun [cited 2017 Mar 8];44(6):110716. Available from:
TE
86. Drewes AM, Jensen RD, Nielsen LM, Droney J, Christrup LL, Arendt-Nielsen L, et al.
EP
Differences between opioids: pharmacological, experimental, clinical and economical
perspectives. Br J Clin Pharmacol [Internet]. 2013 Jan [cited 2017 Mar 8];75(1):6078.
C

AC
87. Olesen SS, Graversen C, Bouwense SAW, van Goor H, Wilder-Smith OHG, Drewes AM.
Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.
Miaskowski C, editor. PLoS One [Internet]. 2013 Mar 1 [cited 2017 Mar 7];8(3):e57963.
Available from: http://dx.plos.org/10.1371/journal.pone.0057963
88. Cahen DL, Gouma DJ, Nio Y, Rauws EAJ, Boermeester MA, Busch OR, et al. Endoscopic
34
ACCEPTED MANUSCRIPT
versus Surgical Drainage of the Pancreatic Duct in Chronic Pancreatitis. N Engl J Med
[Internet]. 2007 Feb 15 [cited 2017 Mar 14];356(7):67684. Available from:
89. Dte P, Ruzicka M, Zboril V, Novotn I. A Prospective, Randomized Trial Comparing
PT
Endoscopic and Surgical Therapy for Chronic Pancreatitis. Endoscopy [Internet]. 2003 Jul
RI
SC
90. Delhaye M, Arvanitakis M, Verset G, Cremer M, Devire J. Long-term clinical outcome
after endoscopic pancreatic ductal drainage for patients with painful chronic pancreatitis.
U
Clin Gastroenterol Hepatol [Internet]. 2004 Dec [cited 2017 Mar 8];2(12):1096106.
AN
91. Seven G, Schreiner MA, Ross AS, Lin OS, Gluck M, Gan SI, et al. Long-term outcomes
M
associated with pancreatic extracorporeal shock wave lithotripsy for chronic calcific
D
pancreatitis. Gastrointest Endosc [Internet]. 2012 May [cited 2017 Mar 8];75(5):997
1004.e1. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0016510712000387

TE
92. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shock-wave lithotripsy of

EP
pancreatic calculi. Gastroenterology [Internet]. 1992 Feb [cited 2017 Mar 8];102(2):61020.

C
93. Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the
AC
management of chronic calcific pancreatitis: a meta-analysis. JOP [Internet]. 2005 Jan 13
94. Moole H, Jaeger A, Bechtold ML, Forcione D, Taneja D, Puli SR. Success of Extracorporeal
Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management: A Meta-Analysis and
35
ACCEPTED MANUSCRIPT
Systematic Review. Pancreas [Internet]. 2016 [cited 2017 Mar 8];45(5):6518. Available
from:
201605000-00004
PT
95. Dumonceau J-M, Costamagna G, Tringali A, Vahedi K, Delhaye M, Hittelet A, et al.
Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy
RI
versus endoscopic treatment: a randomised controlled trial. Gut [Internet]. 2007 Apr 1 [cited
SC
U
96. Inui K, Tazuma S, Yamaguchi T, Ohara H, Tsuji T, Miyagawa H, et al. Treatment of
AN
pancreatic stones with extracorporeal shock wave lithotripsy: results of a multicenter survey.
Pancreas [Internet]. 2005 Jan [cited 2017 Mar 8];30(1):2630. Available from:
M
D
97. Suzuki Y, Sugiyama M, Inui K, Igarashi Y, Ohara H, Tazuma S, et al. Management for
pancreatolithiasis: a Japanese multicenter study. Pancreas [Internet]. 2013 May [cited 2017
TE
Mar 8];42(4):5848. Available from:

EP
201305000-00004
C
98. Tadenuma H, Ishihara T, Yamaguchi T, Tsuchiya S, Kobayashi A, Nakamura K, et al. Long-

AC
term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic
stones. Clin Gastroenterol Hepatol [Internet]. 2005 Nov [cited 2017 Mar 8];3(11):112835.
99. Adamek HE, Jakobs R, Buttmann A, Adamek MU, Schneider AR, Riemann JF. Long term
follow up of patients with chronic pancreatitis and pancreatic stones treated with
36
ACCEPTED MANUSCRIPT
extracorporeal shock wave lithotripsy. Gut [Internet]. 1999 Sep [cited 2017 Mar
100. Ohyama H, Mikata R, Ishihara T, Tsuyuguchi T, Sakai Y, Sugiyama H, et al. Efficacy of
stone density on noncontrast computed tomography in predicting the outcome of
PT
extracorporeal shock wave lithotripsy for patients with pancreatic stones. Pancreas [Internet].
2015 Apr [cited 2017 Mar 8];44(3):4228. Available from:
RI
SC
900000000-99074
101. Dumonceau JM, Devire J, Le Moine O, Delhaye M, Vandermeeren A, Baize M, et al.
U
Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-
AN
term results. Gastrointest Endosc [Internet]. 1996 Jun [cited 2017 Mar 8];43(6):54755.

M
102. Farnbacher MJ, Mhldorfer S, Wehler M, Fischer B, Hahn EG, Schneider HT. Interventional
D
endoscopic therapy in chronic pancreatitis including temporary stenting: a definitive
treatment? Scand J Gastroenterol [Internet]. 2006 Jan 8 [cited 2017 Mar 8];41(1):1117.
TE

EP
103. Rana M V, Candido KD, Raja O, Knezevic NN. Celiac plexus block in the management of
chronic abdominal pain. Curr Pain Headache Rep [Internet]. 2014 Feb 11 [cited 2017 Mar
C
8];18(2):394. Available from: http://link.springer.com/10.1007/s11916-013-0394-z

AC
104. Cuschieri A, Shimi SM, Crosthwaite G, Joypaul V. Bilateral endoscopic splanchnicectomy
through a posterior thoracoscopic approach. J R Coll Surg Edinb [Internet]. 1994 Feb [cited
105. Bouwense SAW, Buscher HCJL, van Goor H, Wilder-Smith OHG. Has central sensitization
become independent of nociceptive input in chronic pancreatitis patients who fail
37
ACCEPTED MANUSCRIPT
thoracoscopic splanchnicectomy? Reg Anesth Pain Med [Internet]. 2011 Nov [cited 2017
201111000-00003
PT
106. Kapural L, Cywinski JB, Sparks DA. Spinal cord stimulation for visceral pain from chronic
pancreatitis. Neuromodulation [Internet]. 2011 Sep [cited 2017 Mar 8];14(5):423-6-7.
RI
SC
107. Fregni F, Potvin K, Dasilva D, Wang X, Lenkinski RE, Freedman SD, et al. Clinical effects
and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain.
U
Eur J Pain [Internet]. 2011 Jan [cited 2017 Mar 8];15(1):5360. Available from:
AN
http://doi.wiley.com/10.1016/j.ejpain.2010.08.002
108. Barrett K, Chang Y-P. Behavioral Interventions Targeting Chronic Pain, Depression, and
M
Substance Use Disorder in Primary Care. J Nurs Scholarsh an Off Publ Sigma Theta Tau Int
D
Honor Soc Nurs [Internet]. 2016 Jul [cited 2017 Mar 8];48(4):34553. Available from:
http://doi.wiley.com/10.1111/jnu.12213
TE
109. Palsson OS, Whitehead WE. Psychological treatments in functional gastrointestinal

EP
disorders: a primer for the gastroenterologist. Clin Gastroenterol Hepatol [Internet]. 2013
Mar [cited 2017 Mar 8];11(3):208-16-3. Available from:

C
AC
110. Thomas D-A, Maslin B, Legler A, Springer E, Asgerally A, Vadivelu N. Role of Alternative
Therapies for Chronic Pain Syndromes. Curr Pain Headache Rep [Internet]. 2016 May 2
111. Ehde DM, Dillworth TM, Turner JA. Cognitive-behavioral therapy for individuals with
38
ACCEPTED MANUSCRIPT
chronic pain: efficacy, innovations, and directions for research. Am Psychol [Internet]. 2014
http://doi.apa.org/getdoi.cfm?doi=10.1037/a0035747
112. McCracken LM, Gauntlett-Gilbert J, Vowles KE. The role of mindfulness in a contextual
PT
cognitive-behavioral analysis of chronic pain-related suffering and disability. Pain [Internet].
2007 Sep [cited 2017 Mar 8];131(12):639. Available from:
RI
SC
200709000-00010
113. Dinges DF, Whitehouse WG, Orne EC, Bloom PB, Carlin MM, Bauer NK, et al. Self-
U
hypnosis training as an adjunctive treatment in the management of pain associated with
AN
sickle cell disease. Int J Clin Exp Hypn [Internet]. 1997 Oct [cited 2017 Mar 8];45(4):417
32. Available from: http://www.tandfonline.com/doi/abs/10.1080/00207149708416141

M
114. Kumar S, Ooi CY, Werlin S, Abu-El-Haija M, Barth B, Bellin MD, et al. Risk Factors
D
Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From
INSPPIRE. JAMA Pediatr [Internet]. 2016 Jun 1 [cited 2017 Mar 8];170(6):5629. Available
TE
from: http://archpedi.jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2015.4955
EP
115. Bchler MW, Friess H, Mller MW, Wheatley AM, Beger HG. Randomized trial of
duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in

C
chronic pancreatitis. Am J Surg [Internet]. 1995 Jan [cited 2017 Mar 8];169(1):65-9-70.
AC
116. Keck T, Adam U, Makowiec F, Riediger H, Wellner U, Tittelbach-Helmrich D, et al. Short-
and long-term results of duodenum preservation versus resection for the management of
chronic pancreatitis: a prospective, randomized study. Surgery [Internet]. 2012 Sep [cited
2017 Mar 8];152(3 Suppl 1):S95102. Available from:
39
ACCEPTED MANUSCRIPT
117. Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, et al. Total
pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from
PancreasFest. Pancreatology [Internet]. 2014 Jan [cited 2017 Mar 8];14(1):2735. Available
PT
from: http://linkinghub.elsevier.com/retrieve/pii/S1424390313008211
118. Chinnakotla S, Beilman GJ, Dunn TB, Bellin MD, Freeman ML, Radosevich DM, et al.
RI
Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation
SC
Lessons Learned From Over 500 Cases. Ann Surg [Internet]. 2015 Oct [cited 2017 Mar
U
AN
201510000-00007
119. Bouwense SAW, de Vries M, Schreuder LTW, Olesen SS, Frkjr JB, Drewes AM, et al.
M
Systematic mechanism-orientated approach to chronic pancreatitis pain. World J

D
Gastroenterol [Internet]. 2015 Jan 7 [cited 2017 Mar 13];21(1):4759. Available from:
http://www.wjgnet.com/1007-9327/full/v21/i1/47.htm
TE
120. Yang CJ, Bliss LA, Schapira EF, Freedman SD, Ng SC, Windsor JA, et al. Systematic
EP
review of early surgery for chronic pancreatitis: impact on pain, pancreatic function, and re-
intervention. J Gastrointest Surg [Internet]. 2014 Oct 19 [cited 2017 Mar 8];18(10):18639.
C
Available from: http://link.springer.com/10.1007/s11605-014-2571-8

AC
121. Yang CJ, Bliss LA, Freedman SD, Sheth S, Vollmer CM, Ng SC, et al. Surgery for chronic
pancreatitis: the role of early surgery in pain management. Pancreas [Internet]. 2015 Jul
201507000-00021
40
ACCEPTED MANUSCRIPT
122. Alexakis N, Connor S, Ghaneh P, Raraty M, Lombard M, Smart H, et al. Influence of opioid
use on surgical and long-term outcome after resection for chronic pancreatitis. Surgery
[Internet]. 2004 Sep [cited 2017 Mar 8];136(3):6008. Available from:
PT
123. Ahmed Ali U, Nieuwenhuijs VB, van Eijck CH, Gooszen HG, van Dam RM, Busch OR, et
al. Clinical outcome in relation to timing of surgery in chronic pancreatitis: a nomogram to
RI
predict pain relief. Arch Surg [Internet]. 2012 Oct 1 [cited 2017 Mar 8];147(10):92532.
SC
Available from:
http://archsurg.jamanetwork.com/article.aspx?doi=10.1001/archsurg.2012.1094
U
124. Riediger H, Adam U, Fischer E, Keck T, Pfeffer F, Hopt UT, et al. Long-term outcome after
AN
resection for chronic pancreatitis in 224 patients. J Gastrointest Surg [Internet]. 2007 Aug 10
[cited 2017 Mar 8];11(8):949-59-60. Available from:

M
http://link.springer.com/10.1007/s11605-007-0155-6
D
125. Mller MW, Friess H, Leitzbach S, Michalski CW, Berberat P, Ceyhan GO, et al.
Perioperative and follow-up results after central pancreatic head resection (Berne technique)
TE
in a consecutive series of patients with chronic pancreatitis. Am J Surg [Internet]. 2008 Sep
EP
C
126. Keck T, Wellner UF, Riediger H, Adam U, Sick O, Hopt UT, et al. Long-term outcome after
AC
92 duodenum-preserving pancreatic head resections for chronic pancreatitis: comparison of
Beger and Frey procedures. J Gastrointest Surg [Internet]. 2010 Mar 22 [cited 2017 Mar
8];14(3):54956. Available from: http://link.springer.com/10.1007/s11605-009-1119-9
127. Weber A, Schneider J, Neu B, Meining A, Born P, von Delius S, et al. Endoscopic stent
therapy in patients with chronic pancreatitis: a 5-year follow-up study. World J Gastroenterol
41
ACCEPTED MANUSCRIPT
128. Demir IE, Tieftrunk E, Maak M, Friess H, Ceyhan GO. Pain mechanisms in chronic
pancreatitis: of a master and his fire. Langenbecks Arch Surg [Internet]. 2011 Feb 10 [cited
PT
2017 Mar 8];396(2):15160. Available from: http://link.springer.com/10.1007/s00423-010-
0731-1
RI
129. Imrie CW. Management of recurrent pain following previous surgery for chronic
SC
pancreatitis. World J Surg [Internet]. [cited 2017 Mar 8];14(1):8893. Available from:
U
130. Lynch ME, Campbell F, Clark AJ, Dunbar MJ, Goldstein D, Peng P, et al. A systematic
AN
review of the effect of waiting for treatment for chronic pain. Pain [Internet]. 2008 May

M
D
200805000-00014
TE
C EP
AC
42
1
ACCEPTED MANUSCRIPT
Appendix:
Recommendations from the Working Group for the International Consensus Guidelines for
Chronic Pancreatitis in collaboration with the International Association of Pancreatology,
PT
American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club
RI
Asbjrn M Drewes1, Stefan A W Bouwense2, Claudia M Campbell3, Gralp O Ceyhan4,
SC
Myriam Delhaye5, Ihsan Ekin Demir4, Pramod K Garg6, Harry van Goor2, Christopher
Halloran7, Shuiji Isaji8, John P Neoptolemos7, Sren S Olesen1, Tonya Palermo9, Pankaj Jay
Pasricha10, Andrea Sheel7, Tooru Shimosegawa11, Eva Szigethy12, David C Whitcomb13 &
U
Dhiraj Yadav13, for the Working group for the International (IAP APA JPS EPC)
Consensus Guidelines for Chronic Pancreatitis
AN
M
1. Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University
D
Hospital, Denmark
2. Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore,
TE
USA
4. Department of Surgery, Klinikum rechts der Isar, Technische Universitt Mnchen, Munich, Germany
5. Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
EP
6. Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
7. Institute of Translational Medicine, University of Liverpool, United Kingdom
8. Department of Surgery, Mie University Graduate School of Medicine, Japan
9. Seattle Children's Hospital Research Institute, Washington School of Medicine, USA
C
10. Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, USA
11. Department of Gastroenterology. Tohoku University Graduate School of Medicine, Japan
AC
12. Visceral Inflammation and Pain Center, Division of Gastroenterology, University of Pittsburgh and UPMC,
Pittsburgh, Pennsylvania, USA
13. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh,
Pennsylvania, USA
2
ACCEPTED MANUSCRIPT
Dhiraj Yadav and Claudia M Campbell
Q1. What is the natural history and burden of pain in chronic pancreatitis (in relation to
treatment)?
PT
Abdominal pain is the most frequent symptom of CP. However, the severity, temporal nature,
and natural history of pain is highly variable (Quality assessment: moderate,
RI
recommendation: strong)
While variation in disease estimates exist, the prevalence of CP has been approximated at
SC
~50/100,000 population(1). Abdominal pain, alone or during episode(s) of acute pancreatitis,
is the most common symptom of CP. Patients typically describe their pain as a dull, sharp or
nagging sensation in the upper abdomen, which can radiate to the back, and often presents
U
after or worsened by food intake. In well conducted natural history studies, pain was observed
as the initial presentation in ~75% of patients(2), and present during the clinical course in 85-
AN
97%(25). The prevalence of pain is influenced by demographic factors and etiology. Patients
with early onset-disease and those with alcohol etiology are more likely to have pain when
compared with patients who have late-onset idiopathic chronic pancreatitis(2,3).
M
Pain experience in an individual patient varies widely during the clinical course of disease.
D
For example, in a multicenter cross-sectional study of 518 chronic pancreatitis patients of all
etiologies, no, mild-moderate, and severe pain in the preceding year was reported by 15.6%,
TE
17.6% and 66.8% patients respectively. Among patients with pain, 38% reported intermittent
pain, and 62% constant pain. Among those with constant pain, only 7% experienced constant
severe pain that did not change over time(6). Interestingly, the duration of disease did not
EP
influence the pain experience(7). During longitudinal follow-up of 207 patients with alcoholic
chronic pancreatitis, two patterns of pain were observed type A and type B(8). Type A pain
was described as episodes, which could last for up to 10 days at a time with pain free intervals
C
lasting up to several months. Type B pain was described as prolonged periods of persistent or
recurring pain with no pain free intervals, often requiring repeated hospitalizations. Patients
AC
who had only type A pain (44%) were managed medically, while those with type B pain
(56%) underwent surgical intervention to achieve pain relief followed by either pain free
intervals or a change of pattern to Type A pain(8). A similar empiric analysis has not been
conducted in patients with non-alcoholic etiologies, but it is likely that the natural course in
these patients also has similar variability in pain patterns during the clinical course.
Whether and what fraction of patients achieve a complete and lasting pain-free status during
the course of disease remains a matter of debate. According to the burn-out hypothesis,
irrespective of the type of treatment received, a majority of patients with chronic pancreatitis
achieve lasting pain-free status during the clinical course(3,8). This claim, however, has not
3
ACCEPTED MANUSCRIPT
been substantiated by others, mainly due to persistence of pain symptoms in a significant

fraction of patients with ongoing pain even after 10 or more years of disease(9). The
prevalence of pain seems to decrease with progression of morphological (e.g. calcifications)
and functional changes (e.g. endocrine and exocrine insufficiency), however, this does not
PT
guarantee a transition to pain-free status(3,5,8).
Continued alcohol consumption is linked with disease progression(10), and increases the
RI
frequency of pain episodes in patients with established chronic pancreatitis(11). Although no
empiric data specifically associates tobacco smoking to the pain experience, given the role of
tobacco in disease progression(12), it is conceivable that it may have an indirect and negative
SC
effect on pain.
The underlying mechanisms responsible for producing pain in chronic pancreatitis are
U
unclear. Pain could be related to status of the pancreas (e.g. acute or chronic inflammation,
pancreatic ductal obstruction from stones and/or stricture), peripancreatic structures (e.g.
AN
common bile duct stricture, gastric outlet or duodenal obstruction) or local complications (e.g.
pseudocyst). In a subset, no obvious structural cause is apparent. Similar to other pain
conditions, little association exists between pain report and morphological characteristics in
M
chronic pancreatitis patients(6). Thus, other factors clearly play a role in individual patients
pain experience. Studies to systematically evaluate risk factors for the development of pain
D
and examination of pain course and patterns are warranted. Such work may lead to the
formulation of novel treatments that could potentially be deployed proactively to intervene for
TE
patients suffering with painful chronic pancreatitis.
Naturally, CP is a major burden for the patients and it is regarded the most severe
EP
complication to the disease. Accordingly, both pain intensity and the frequency of pain attacks
have been shown to reduce life quality in patients with CP(7,13). A recent large study, using
SF12 questionnaire, found pain to be the single most important predictor of quality of life in
C
CP. When compared with patients with no pain, those with constant pain had a 5 (in the
absence of severe pain) or 10-point (in the presence of severe pain) reduction in physical, and
AC
7-point reduction in mental quality of life (a difference of 3 or more points is clinically

relevant) (14).
4
ACCEPTED MANUSCRIPT
Pankaj Jay Pasricha, Sren Schou Olesen and Eva Szigethy
Q2. Are there different types of pain in CP and what does it mean for treatment?
PT
Pain in CP remains poorly understood and inadequately correlated with neurobiological
mechanisms. By definition, CP is characterized by inflammation but unlike other
inflammatory disorders, there is a paucity of therapeutic attempts targeting this particular
RI
aspect of pathophysiology. On the other hand, there are striking changes in structure and
function in both the peripheral and central nervous system in this condition, lending
plausibility to a maladaptive state that includes both neuropathic and dysfunctional pain. In
SC
the absence of effective anti-inflammatory approaches, it is clearly important to focus on the
alteration of function that accompanies these changes in the nociceptive system as a potential
therapeutic target. (Quality assessment: low; Recommendation: strong; Agreement: strong)
U
AN
Pain in chronic pancreatitis is difficult to manage for multiple reasons as described several
times in this position paper. A significant factor in this regard is the heterogeneous and
multiplex nature of pain, representing different drivers (anatomical, inflammatory, primary
M
neurobiological, psychosocial), locations (peripheral, central), and confounding factors

(pharmacological dependence and aggravation). This chapter will attempt to provide a
D
classification based on the etiopathogenesis of pain in the hope that it will provide the basis of
more rational approach to treatment.
TE
General biological categories of pain

As reviewed by Woolf, pain can be classified broadly in terms of utility to the living being as
EP
either being adaptive/protective or maladaptive/pathological(15). Adaptive pain serves the

organism by helping it to avoid harm from environmental or internal insults. Thus pain in
response to a prick or contact with a hot object warns us of the possibility of serious injury
C
and is the purest manifestation of the nociceptive response. In the clinical context, the most
common form of pain can also be considered adaptive occurring in response to tissue injury of
AC
various origins (mechanical, chemical, infectious, immunological etc.), with accompanying

inflammation that results in hypersensitivity (sensitization) of the nociceptive system. Such a
pain is also adaptive in that it either results in seeking attention for it or causes avoidance of
physical contact/movement that could interfere with healing and/or aggravate the injury.
The other broad category of pain can be considered maladaptive, in that it does not serve a
useful purpose, as it is no longer linked to ongoing injury or pain in the relevant tissue.
Instead, the pain is believed to result from either damage (neuropathy) or dysfunction to the
nociceptive system itself, which is now behaving pathologically (hence the name).
5
ACCEPTED MANUSCRIPT
Clinical patterns of pain in chronic pancreatitis

An early approach to classifying pain in chronic alcoholic pancreatitis was made by Amman
et al based on the clinical pattern in a cohort of 207 patients followed prospectively with both
surgical and conservative management(8). A-type pain pattern, with one or more discrete
PT
episodes of pain interspersed with pain-free intervals of several months to years, was
observed in all patients in their series. Slightly less than half (44%) of patients also had B-
type pain described as persistent (i.e. daily) pain over prolonged periods of time and/or
RI
closely clustered exacerbations of severe pain, with the typical case having severe pain 2 or
more days per week for at least 2 months and requiring repeated hospitalizations in most
instances.
SC
A more recent study by the North American Pancreatic Study (NAPS) group also studied a
prospectively followed cohort of 414 patients of mixed etiology (nearly half of whom were
U
thought to be alcoholic in etiology) and attempted to classify pain according to temporal and
severity criteria, and correlate these with quality of life, resource utilization and pain-
AN
associated complications(7). Although their parsing of pain categories was more nuanced, it
appears that alcohol, tobacco use as well as most meaningful clinical outcomes including
quality of life were best predicted when intermittent (about 45% of patients) versus
M
constant pain were compared, thus echoing the earlier binary classification. However, it
should be pointed out the descriptions in these two papers are not strictly comparable: the
D
NAPS2 data is more based on patient recall of their pain pattern at a single time point whereas
the study by Amman et al gathered this information by longitudinal observation of their
TE
patients.
Pattern of pain CP and correspondence with putative neurobiological causes

EP
Inflammatory Pain
It is intuitively appealing to suggest that a significant, if not major, type of pain in CP is
inflammatory in nature, whether or not associated with mechanical/space-occupying lesions
C
such as ductal dilation or pseudocysts. However, a more rigorous analysis would require
consideration of the following issues before coming to a final conclusion:
AC
1. Biological plausibility. Dolor (pain) is a cardinal feature of inflammation and the

biological and clinical evidence linking the two is incontrovertible in general. The
development of animal models to study pain in CP has also shown that inflammatory
pain in CP is mechanistically generally similar to other chronic inflammatory
conditions. The expression of numerous algogenic factors is altered in experimental
models as well as in human pancreatic specimens obtained from patients with CP upon
surgery. These molecules include NGF and its high affinity receptor (TrkA)(16,17),
TRPV1(18), as well as SP and its receptor, NK-1(16,19,20), CGRP(19), BDNF(21) as
well as other neurotrophic factors such as artemin and its receptor GFR3(22).
Elevated levels of PGE2 have recently been found in the pancreatic secretions of
6
ACCEPTED MANUSCRIPT
patients with early CP who have significant pain but no clear structural
abnormalities(23). Some but not all of these have been shown to correlate with pain
severity (also see below), although causation is not proven. Nevertheless, these studies
have been very valuable in supporting and strengthening evolving theories on the
PT
neural pathogenesis of pain in chronic pancreatitis, in keeping with what we have
learnt from animal models(24).
2. Coincidence between inflammatory and painful exacerbations in time. If this was
RI
true, it would follow that the intermittent episodes of pain observed in patients
correspond to a flare of inflammation. Many of these patients are hospitalized for
pancreatitis during such episodes so such a connection is certainly plausible,
SC
although the literature does not actually provide evidence of correlation with
established biomarkers of inflammation. With persistent pain patterns, the association
with inflammation is even more controversial. In their paper, Amman et al state that,
U
type B pain was thought to most often result from a potentially correctible cause -
pseudocysts (54%), obstructive cholestasis (24%) and presumptive ductal
AN
hypertension (14%), with prompt relief by a drainage procedure(8). However, these
results probably reflected the surgical bias in their series, as they have not been borne
out by others. In a large prospective cohort study conducted by the NAPS2
M
consortium, there was no correlation between temporal pattern and the presence or
absence of radiological evidence of inflammation or obstructive pathology. Indeed,
D
many patients with CP but no pain had similar findings than those with pain(7).
3. Correlation between severity of inflammation and pain
TE
There are two lines of evidence on this subject, with seemingly conflicting results. The
first comes from careful histological examination of pancreatic specimens from
patients with CP showing correlation between the expression of several inflammatory
EP
biomarkers or cell types with pain. Immune cells are abundantly found in CP and their
products including cytokines such as IL-8 and chemokines such as fractalkine are
strongly implicated in neural responses and correlate with pain intensity in
C
humans(25,26). Mast cells are also increased in chronic pancreatitis in humans(27)

and patients with painful CP demonstrated a 3.5-fold increase in pancreatic mast cells
AC
as compared with those with painless CP(28).

On the other hand, and in contrast to the earlier studies by Amman et al(8), the largest
prospective study to date using modern radiological techniques found no evidence that
either pain severity or temporal pattern correlates with inflammatory changes on
imaging(6). Other smaller studies also provide support for the contention that
morphological changes do not correlate with pain(29).
4. Attenuation of pain with lessening of inflammation by natural history, medical or
surgical intervention. A recurring controversy in the field has been whether pain in
CP recedes. In the study by Amman et al, pain patterns were more evident early in the
course of the disease and with time both apparently gradually dissipated. Hence, more
7
ACCEPTED MANUSCRIPT
than 80% of patients with alcoholic pancreatitis were pain-free 10 years after the onset
with the same proportion of patients also exhibiting severe pancreatic insufficiency; at
this stage about 50% were diabetic, presumably reflecting endocrine failure(8). This
has led this group to champion the so-called burn-out theory for pain in CP;
PT
however no evidence exists that it is actually the inflammation that is burnt out instead
of just functional pancreatic parenchyma. Further, others have refuted this, most
convincingly by the NAPS2 study, which showed that neither pain pattern nor severity
RI
changed with the duration of the disease, albeit based on patient recall data(7).
Another way to approach this relationship is to examine therapeutic trials with
SC
interventions directed primarily at inflammation. Unfortunately, there is a paucity of
such interventions with anti-oxidants being the most studied class of agents, under the
reasonable assumption that this will be associated with a reduction in inflammation. A
U
Cochrane review of 12 such studies concluded that there was a slight reduction in the
intensity of pain but no change in the proportion of patients that were pain free, thus
AN
making it difficult to draw a firm conclusion(30).
It is much more difficult to use surgical or endoscopic approaches in this way as

M
determining any effect of putative reduction in inflammation from these interventions

would be seriously flawed by the presence of multiple and complicated confounding
D
factors. Even so, there have been no studies that directly examine the relationship
between the degree of inflammation found at pancreatectomy and subsequent pain
TE
relief (although there are several descriptions relating this to pre-surgical pain status,
as described above).
EP
Neuropathic and Dysfunctional Pain

Evidence from animal models has provided convincing evidence that CP results in
hypersensitivity of pain responses to pancreatic stimulation, associated with
C
impressive sensitization of the primary nociceptive neuron with specific

electrophysiological and molecular changes (such as a reduction in the IA current and
AC
changes in the expression of TRPV1, neuropeptides and other factors). These appear
to be driven by factors in the milieu of CP such as NGF and more recently,
TGF(24,31). Animal models also suggest a component of central sensitization
including potential roles for spinal glial activation and descending inhibitory pathways
facilitated by the rostral ventromedial medulla (RVM)(3234).
Corresponding evidence for humans with CP is also beginning to emerge. Patients

with severe CP have lower pain and expanded pain referral areas thresholds than
patients with moderate CP or healthy volunteers, as measured by pressure and electric
stimuli in selected dermatomes, reflecting somatic hyperalgesia and allodynia, which
8
ACCEPTED MANUSCRIPT
is a reflection of spinal sensitization(35,36). Alterations in descending inhibitory

influences on spinal nociceptive neurons have been inferred based on changes in
sensation at remote sites(3538). (Electroencephalograpy (EEG) in patients with CP
show functional changes suggesting a maladaptive pain response(36,3941).
PT
In addition to functional changes, there are also morphological effects of CP on the
nervous system. This is best demonstrated by the changes in neural density,
hypertrophy and both peri- and endo-neural inflammatory infiltration in resected
RI
clinical specimens(42). The CNS may also be affected as seen by microstructural
changes in cingulate and prefrontal cortices. Remarkably, there were differences in
brain imaging between patients with episodic versus continuous pain as well as overall
SC
correlations between MRI findings and pain scores(43).
Mechanical causes of pain.
U
In some cases of chronic pancreatitis, pain may likely be due to large space occupying
lesions such as pseudocysts or cancers, or ductal obstruction from strictures or stones.
AN
Presumably this kind of pain results from activation of mechanosenstive nociceptive
nerves and may represent another primary mechanism in some instances. More often,
however, these lesions trigger or exacerbate pain on a background of a nociceptive
M
system that has been sensitized by inflammatory or neuropathic mechanisms as

discussed above.
D
Conclusions, Perspective and Future Directions

TE
Pain in CP remains poorly studied and inadequately correlated with neurobiological

mechanisms. By definition CP is characterized by inflammation but unlike other
inflammatory disorders, there is a paucity of therapeutic attempts targeting this
EP
particular aspect of pathophysiology, rendering it difficult to understand how much it

contributes to pain. On the other hand, there are striking changes in structure and
function in both the peripheral and central nervous system in this condition, lending
C
plausibility to a maladaptive state that includes both neuropathic and dysfunctional

pain. In the absence of effective anti-inflammatory approaches, it is clearly important
AC
to focus on the alteration of function that accompanies these changes in the

nociceptive system as a potential therapeutic target.
Pain is a complex and multifactorial phenomenon that affects every aspect of a patients life,
including emotional, social and physical functioning, and correlates with quality of life in
CP(13). Because patients with CP have not been systematically followed using a
comprehensive and multidisciplinary approach, it is important to gain an understanding of
each of these components, particularly as each has been shown to have relevance in other
chronically painful conditions. This is best accomplished by a longitudinal multi-center
registry that prospectively studies the outcomes of medical and surgical care of patients with
9
ACCEPTED MANUSCRIPT
CP, identifies biomarkers for inflammation and provides correlation with histological and
molecular changes in pancreatic tissue. Of particular interest are questions that emphasize
persistent pain, flare-ups and disability. Such an approach will increase our understanding of
the etiology of pain in CP, allow the identification of high-risk subgroups for testing
PT
medical, surgical, and possibly psychosocial treatment in future clinical trials, and ultimately
increase our ability to personalize treatment to the individuals risk and clinical profile.
RI
Claudia M Campbell and Pankaj Jay Pasricha
Q3. Which methods are available to assess pancreatic pain and its response to
SC
treatment?
Assessment of pain in CP follows the guidelines for other types of chronic pain, where the
multidimensional nature of symptom presentation is taken into consideration. Only a few
U
instruments have been validated for subjective pain assessment in CP; however, several
appropriate measures exist despite not being rigorously validated in this population. (Quality
AN
assessment: moderate; Recommendation: strong; Agreement: strong)
Pain is complex in nature and interacts with multiple systems, thus systematic, frequent
M
multidimensional pain assessment is required to determine the most efficacious treatment

plan, and evaluate effects for patients presenting with pain(44,45). As in many idiopathic pain
D
conditions, CP pain is challenging to assess and treat in, for example perceived pain severity
may be completely unrelated to observed physical manifestations or symptoms. Given that
TE
individual differences in the development, course, and sequelae of a given pain condition are
broad, and that observable physical pathology (e.g., duct dilation, atrophy, calcifications)
correlates minimally with pain-related symptomatology(6), other factors must play a role in
EP
either facilitating or protecting against the experience of long-term, disabling pain. In addition
to pain intensity, which is the only routinely reported outcome in most previous CP studies,
assessment of a number of qualities describing the dimensions and characteristics of pain is
C
crucial, including documenting functional impairment and quality of life(46). These

dimensions are described briefly below along with comments on different scales and
AC
frequently used questionnaires that can be used during pain assessment. Additional, somewhat
more objective, methods for visualizing or assessing pain are also included along with a
discussion of complicating factors and barriers to effective pain management.
Pain Dimensions for assessment:

CP patients often describe their pain as severe, unremitting, exacerbated by eating and
sometimes associated with post-prandial nausea and vomiting(47). Patients also frequently
report breakthrough pain or enhanced pain during a flare-up which is sudden, unexpected
and more intense than their baseline chronic pain level. Both of these distinct pain types
should be assessed with regard to the following qualities.
10
ACCEPTED MANUSCRIPT
Etiology of pain (with respect to onset of symptoms). While diagnoses based on etiology is
the current standard in chronic pain, some have suggested that a better approach to
assessment, diagnosis, and treatment may be to identify the pathophysiologic mechanisms that
account for a patient's pain and to then use these mechanisms as the basis for selecting the
PT
most appropriate approach to treatment(48,49). While the pathophysiology of CP is unclear,
the individual etiology may hint at specific mechanisms and a potential course.
Pain duration and chronicity should be evaluated by assessment of the onset and progression
RI
of pain over time. It may or may not coincide with the onset of other CP symptoms.
Categorizing the pain into intermittent acute, continuous or combined might be appropriate. If
the pain has persisted for greater than three months it is considered chronic(50) . As for
SC
breakthrough pain, duration may be more limited and time locked to meals, stress, alcohol
intake, elimination, etc. A large CP study, conducted approximately five years ago, found that
the temporal nature of pain was a more influential determinant of healthcare utilization and
U
health-related QOL when compared to pain severity(7). Early diagnosis and treatment is
important in CP, as repeated episodes of inflammation may produce irreversible damage, and
AN
pain relief may be less effective the longer the disorder is left untreated.
Pain Intensity is subjective in nature and may vary strongly from person to person as a
function of individual differences in pain sensitivity, activity level, diet, substance use, coping
M
strategies, and the severity of the underlying disease, among other factors, many of which are
likely yet unknown factors that may vary by the individual. Typically, intensity is queried on
D
a 0-10 numerical pain rating scale where 0 = no pain and 10 = the worst pain you can
imagine(51). Disease severity, different, but related to pain intensity is most commonly
TE
categorized in CP based on the Cambridge Classification system which divides CP into five
severity groups based on morphological changes of the main pancreatic duct and its side
branches based on ERCP, ultrasound and CT(52). A more recent classification of CP
EP
incorporates risk factors into a categorization schedule, not specifically linked to severity.
TIGAR-O evaluates and categorizes CP into toxic-metabolic, idiopathic, genetic,
autoimmune, recurrent and severe acute pancreatitis or obstructive(53).
C
The Quality of pain, a subjective description provided by the patient, may hint at the type of
pain they are experiencing. For example, pain described as burning, pins and needles
AC
feeling, etc. may be indicative of neuropathic pain, which may be under evaluated/treated in
CP patients(47). Pain described as squeezing, pressure, cramping, distention, dull, deep, and
stretching is usually visceral in origin. Visceral pain is most commonly recognized in CP
patients, with pain that emanates from the viscera, is diffuse and difficult to localize and
involves intense motor and autonomic reactions. It is also important to evaluate both the
severity and quality of pain not only at rest or during a crisis, but to query these dimensions
having the participant reference when they are standing, laying down, during movement,
when using the bathroom and on palpation of the abdomen.
Associated/Aggravating/Alleviating factors. Frequently diarrhea, nausea and vomiting
accompany pain in CP, particularly breakthrough pain. Understanding what symptoms are
11
ACCEPTED MANUSCRIPT
associated with pain and when they occur in relation to pain, and what factors make it worse
or improve it may bring insight into appropriate treatment recommendations. For example, if
dietary, or other lifestyle factors play a role in aggravating symptoms, these would be a good
place to start. Avoiding alcohol consumption, smoking and reducing fatty food consumption
PT
may all improve pain in CP (see treatment sections within these guidelines). Stress and
anxiety frequently impact pain and patients who experience this connection may benefit from
stress-reduction strategies or psychological interventions aimed at reducing such qualities.
RI
Similarly, factors that reduce pain should be queried, such as application of heat, relaxation,
distraction, etc. as they could potentially be applied early in a flare.
If alcohol issues are noted, it is warranted to delve deeper into the specifics of alcohol use,
SC
given the association between alcohol consumption and CP. If current alcohol use is endorsed
or suspected, conducting a CAGE questionnaire (asking 1) have you felt the need to Cut down
on your drinking?; 2) Have people Annoyed you by criticizing your drinking?; 3) Have you
U
ever felt Guilty about drinking?; 4) Have you ever felt the need for an Eye-opener a drink
first thing in the morning to steady your nerves or get rid of a hangover) may aid in screening
AN
for problematic drinking behaviour.
Mood is another important factor to consider and assess in CP. CP patients endorse significant
difficulties in mood, social and emotional functioning. Depressive symptoms have been
M
related to participants' reports of increased pain and decreased quality of life, with recent
work suggesting that greater than half of CP patients may score above the cutoff for clinically
D
significant depressive symptomology(54), which potentially warrants psychological

evaluation and treatment. Of interest, they also found that clinically significant depression
TE
was strongly associated with greater pain severity and reduced physical and mental quality of
life. While stress is a well-documented factor in flare ups, little research has focused on the
role of anxiety or its relationship to pain or quality of life in CP. Pain catastrophizing, a
EP
negative cognitive and affective processes related to pain, characterized by helplessness,

magnification and rumination about pain symptoms, is a risk factor for long-term pain and
disproportionately-negative sequelae of pain (e.g., high levels of physical disability or
C
healthcare costs)(55) in a variety of clinical pain conditions. Catastrophizing has been

implicated as an etiologic or prognostic factor in a number of persistent pain(5661), higher
AC
pain and disability following surgery(6265), longer recovery times(66), and less
improvement in pain(67). Thus, catastrophizing may well be an important prognostic factor in
CP, but a dearth of information exists in regards to catastrophizing in CP patients.
The impact on quality of life is also important to evaluate and is clearly important in patients
with CP(13,68). Inquiring about changes in appetite, physical activity, relationships, family
functioning/functioning within the household, sexual functioning, irritability, sleep, anxiety,
anger, depression and concentration will aid in understanding the pain experience in each
individual. A number of these factors have bidirectional relationships with pain which could
represent modifiable risk factors that could be improved and reduce pain. Sleep for example,
is well known to be disturbed by pain, but recent work also identifies sleep as an independent
12
ACCEPTED MANUSCRIPT
modulator of pain perception; thus disturbed sleep could exacerbate the following days pain
creating a vicious cycle(69,70). In order to evaluate the impact of pain on patients quality of
life, the EORTC QLQ-C30 and QLZQ-PAN26 questionnaires have been formally examined
and validated for CP patients(71).
PT
Central Sensitization
RI
Pain processing occurs in the central nervous system, where nociceptive input can be
inhibited or facilitated and which can undergo both functional and structural plasticity(72).
When plasticity results in amplification of pain, this central sensitization (CS) represents a
SC
rewiring that can include inhibition of descending pain modulation and/or changes in
connectivity(73), including changes to forebrain circuits involved in emotion and
cognition(74). Central sensitization is implicated as a mechanism of pain chronification
U
(transition from acute to chronic pain), amplification, and maintenance in a number of chronic
pain conditions(73). In humans, CS manifests as hyperalgesia, allodynia, and spreading of
AN
pain and can be reliably assessed in laboratory studies through application of noxious stimuli
(see below)(73). A growing literature implicates central sensitization in CP. Repeated and
prolonged pain attacks influence the central nervous system and have been shown to alter
M
brain regions in CP(36). This may be one reason that abdominal imaging or other
physiological findings do not correspond with the reported level of pain(6). It may also factor
D
in to why pain persists in approximately 30% of patients even after total

pancreatectomy(75,76).
TE
Types of assessment
Subjective verbal reports of either a single- or multi-dimensional scale are most common for
EP
pain assessment. However, additional methods for evaluating pain, and pain sensitivity are
being increasingly employed in CP patients. While single-dimensional verbal reports of pain
severity are the norm in the literature, a number of questionnaires have been developed for a
C
more comprehensive pain assessment. For example, the WILDA (words to describe pain,
intensity, location, duration, aggravating/alleviating factors)(77) pain assessment tool may be
AC
useful to aid in this assessment. A commonly used measure in CP, the Izbicki pain score was
developed to capture some of the aforementioned dimensions of pain and provide a surrogate
score based on the pain attack frequency, pain intensity score (VAS), analgesic use, and
duration of disease-related inability to work(78). It has, however, never been strictly validated
in patients with CP. Future work should consider truly validating this measure in a large
sample, particularly since it has become the default pain assessment measure in CP.
Subjective Verbal Reports

One-dimensional scales (usually pain intensity)
13
ACCEPTED MANUSCRIPT
One-dimension scales assess a single element of pain, but provide allow for a simple and fast
method for patients to self-report the subjectively experienced intensity of their pain. Use of
such scales is appropriate in settings of acute pain when the etiology is clear; however, they
can oversimplify the pain experience(79).These scales use numeric (often 0-10), verbal (eg,
PT
mild, severe or other verbal descriptors like discomforting, excruciating) or visual (pictures
of faces, most typically used with children or the cognitively impaired) descriptors to quantify
pain or the degree of pain relief. Numerical scales, such as the visual analogue scale (VAS),
RI
are commonly applied to assess the intensity of pain in CP patients, but should be combined
with a standardized registration of the pain pattern in time including the frequency of pain
exacerbations(7).
SC
Multidimensional scales
Multidimensional scales measure several of the above overviewed aspects of pain, including
its intensity, nature and location, and in some cases, pains impact on mood or activity
U
level/physical functioning. Evaluating these variables is integral in overall pain assessment
and management. Multidimensional scales are valuable in complex or persistent acute or
AN
chronic pain cases when intensity needs to be assessed as well as other factors such as quality
of life, social support, interference with activities of daily living, and mood. The Brief Pain
Inventory (BPI) is one such scale that is commonly used with chronic pain patients and
M
relatively quick. It quantifies pain intensity as well as mood, ability to work, relationships,
sleep, enjoyment of life, and the effect of pain on general activity. The BPI also has the ability
D
to evaluate the progress of a patient with a progressive disease and provides an opportunity to
evaluate improvement or decline in the assessed domains. BPI scores were recently correlated
TE
with quality of life in CP patients, not surprisingly suggesting that the more severe ones pain,
the worse their quality of life(13).
The McGill Pain Questionnaire is another commonly used survey that assesses three aspects
EP
of the pain experience, including sensory, affective, and evaluative dimensions. These
components are subdivided into subclasses that represent varying degrees of pain. Seicean and
colleauges(80) note that the McGill is a more appropriate pain assessment measure that
C
unidimensional numeric scales alone in CP patients.

AC
Quantitative Sensory Testing (QST)

Despite tremendous individual differences in clinical outcomes among patients with
pancreatitis and the experience of almost daily pain (in approximately 55% of patients(24)),
very little is currently known about pain phenotypes in pancreatitis and how these phenotypes
predict clinical outcomes. Pain sensitivity and CS can be reliably assessed and quantified in
the laboratory using quantitative sensory testing (QST)(73). These calibrated and standardized
methods for delivering noxious stimuli under controlled conditions(81) are reflective of
clinical conditions, as subjects who rate QST stimuli as most painful(82,83), or show
heightened CS(84,85) report the most frequent, disabling clinical pain. QST often assess pain
thresholds, which has been shown to be stable over time in CP(86), although more
14
ACCEPTED MANUSCRIPT
sophisticated, dynamic psychophysical techniques have the potential to more directly assess
CNS pain-modulatory processes(87). Since incoming nociceptive input is actively regulated at
multiple levels of the neuraxis, from spinal cord to cortex(88,89), it is important to understand
individual differences in CNS pain-facilitatory and pain-inhibitory processes, which maps on
PT
to pain chronification and the variability reported among chronic pain patients(90).
Participants who rate such calibrated noxious stimuli as most painful(82,83), who show the
greatest CNS sensitizability(84) and the least endogenous pain inhibition(85), report the most
RI
frequent, disabling daily pain complaints (e.g., headaches, backaches, etc.). Such pain-
sensitive individuals (i.e., lower pain threshold, higher pain ratings of standardized noxious
stimuli) also obtain the least benefits following multidisciplinary treatment for chronic
SC
pain(91), experience enhanced acute postoperative pain in a number of surgical
procedures(9299), are at risk for developing chronic pain following surgery(100,101), and
derive reduced analgesic effects from opioids(102).
U
QST, along with other mechanistic-based techniques in CP patients was recently reviewed by
Bouwense and colleagues(103); we refer the reader to their work for a more comprehensive
AN
overview. CP patients have documented hypoalgesia to visceral and somatic stimulation from
tonic and phasic mechanical stimuli compared to healthy controls(104), hypersensitivity to
mechanical stimulation of the skin(105), and higher cortical activity than controls in specific
M
bands when the esophagus is electrically stimulated to pain threshold, suggesting involvement
of neuropathic pain mechanisms(106).
D
Central sensitization in CP was hypothesized and examined using QST over a decade ago(37)
and has received additional attention, evaluation and documentation through assessment of
TE
conditioned pain modulation and widespread pain(36,38), pain facilitation and referred pain to
electrical stimulation(105), repeated electrical stimulation to the skin (reflective of pain
facilitation)(104), as well as positive trials of pharmaceutical treatments known to impact
EP
central sensitization(107109). For example, QST, being frequently employed to evaluate

treatment responses, evaluated among CP patients, was found to elicit increased electrical
pain detection and tolerance, as well as pressure pain tolerance following a three-week course
C
of pregabalin as compared to placebo, suggesting inhibitory effects of the hyperalgesic

spreading component of central sensitization(108). Additionally, oxycodone was found to be
AC
more effective than placebo and morphine on mechanically and thermally evoked pain
stimulation as well as oesophageal heat pain(110). A particularly elegant study recently found
that QST responses were able to predict the analgesic efficacy of pregabalin in CP
patients(107) with solid classification accuracy (84%).
Biomarkers for pancreatic pain and pain severity

Several studies from the same group of investigators suggest a correlation between
inflammatory, neuropathological and expression of certain biological factors and severity of
pain(111). However, this is based on access to resected pancreatic tissue and so is not a
practical biomarker. On the other hand, there is some promise in analysing pancreatic juice
15
ACCEPTED MANUSCRIPT
obtained at endoscopy for cytokines and small molecules- elevated levels of PGE2 have
recently been found in the pancreatic secretions of patients with early chronic pancreatitis
who have significant pain but no clear structural abnormalities(23). Further studies are needed
to validate this and other molecules in a broad spectrum of patients. Finally, there are several
PT
CNS markers that may be affected in CP and perhaps provide a so-called biomarker for pain
in this condition. Electroencephalograpy (EEG) in patients with CP show functional changes
suggesting a maladaptive pain response(3941). The CNS may also be affected as seen by
RI
microstructural changes in cingulate and prefrontal cortices with differences noted in brain
imaging between patients with episodic versus continuous pain as well as overall correlations
between MRI findings and pain scores(68).
SC
Conclusions
Ongoing, comprehensive and multidimensional pain assessment is integral in CP and the
U
factors overviewed here would be appropriate measures to include in such an evaluation.
These variables and assessment of the type of pain a CP patient is experiencing (visceral,
AN
neuropathic, central, etc. and any overlap) may aid in treatment planning. While an in-depth
and thorough QST assessment may not be realistic for everyday clinical use in CP patients,
brief, mobile bedside assessments are available for classifying patients with other chronic
M
pain conditions(112114) and may be useful in CP. Such assessment has the potential to aid
in a mechanistic approach to personalized treatment and the tracking of tangible outcomes.
D
TE
C EP
AC
16
ACCEPTED MANUSCRIPT
Eva Szigethy & Pramod Kumar Garg
Q4. What is the role of smoking and alcohol on pain treatment in CP

Abstinence from alcohol and smoking, in addition to adequate treatment, should be strongly
PT
advised in patients with CP (Quality assessment: moderate (alcohol) to weak (smoking);
Recommendation: strong; Agreement: strong)
RI
Alcohol: Pain is the most common symptom in chronic alcohol- related pancreatitis. While
high alcohol intake is a risk factor for pancreatitis, this relationship relative to acute and
chronic pancreatitis has recently been established. In a meta-analysis of 7 association studies
SC
with 157,026 participants and 3618 cases of pancreatitis(115), the dose-response relationship
between average volume of alcohol intake and chronic pancreatitis was monotonic in both
men and women and for acute pancreatitis in men. The relationship was highly significant,
U
but non-linear for acute pancreatitis in women. Compared to abstinence, there was a
significant reduction of risk of acute pancreatitis in women below a threshold dose of 40g per
AN
day, but not for men. Alcohol consumption at a higher daily dose increased the risk of any
type of pancreatitis.
Recurrence of pancreatitis is high among patients with alcohol related acute pancreatitis. In a
M
study of 562 patients in Finland the recurrence rate was 46% over 1-20 years(116). Similarly,
3748% recurrence rates have been reported in other studies(117,118). Prospective studies
D
evaluating the effects of cessation on chronic pain are lacking, but even in the absence of a
direct causal relationship with CP-related pain, the health risks of alcohol use, including
TE
acceleration of disease progression, still makes abstinence advisable.
For treatment of alcohol-related pancreatitis, abstinence from alcohol is associated with

EP
reduction in frequency of recurrence of pancreatitis. In a prospective observational study,

patients with first attack of alcoholic acute pancreatitis were followed-up for 2 years; out of
51 patients, 13 who remained abstinent at 2 years had no recurrence compared with compared
C
with 17 patients with continued alcohol consumption(119). In a randomized controlled trial,

120 with alcohol-associated AP were randomized either to repeated intervention or initial
AC
intervention only for alcohol abstinence. Alcohol abstinence in the repeated intervention
group resulted in significant reduction in recurrence of pancreatitis (9 vs. 20 episodes)(120).
The authors followed up these patients to study the long-term outcome of patients who
abstained. Of the 118 patients, 18 who remained abstinent had no further attack of pancreatitis
during a mean follow-up of mean 5 years, compared to 34% of the 100 non-abstinent patients
who had at least one recurrence during the follow-up(121).
Pharmacological treatment is often necessary to ensure that the patients refrain from alcohol
intake. Benzodiazepines remain the gold standard to reduce symptoms of alcohol withdrawal
including seizures and delirium tremens(122,123). Long-term use of benzodiazepines carry
the risk of abuse, addiction and liver toxicity. Mood stabilizers such as carbamazepine are
17
ACCEPTED MANUSCRIPT
safe and efficacious in treating moderate symptoms of alcohol withdrawal(123,124). It is

important that severe withdrawal be treated in a hospital setting or facility where 24-hour
monitoring is available for delirium tremens or seizures. Only three medications have FDA-
approval to treat alcohol dependence; naltrexone, acamprosate and disulfiram. Naltrexone has
PT
strong support in reducing relapse in alcoholics(125), while acamprosate has shown efficacy
in some(126) but not all trials(127). More recent research has found that functional genetic
polymorphisms may predict who does and does not respond to treatment such as naltrexone
RI
for alcohol dependence(128). One large-scale study evaluated the efficacy of pharmacological
(naltrexone versus acamprosate versus both and/or placebos in combination with medical
management with or without behavioral therapy for alcohol dependence(127,129). Previous
SC
medical management of alcohol dependence and either behavioral therapy, naltrexone, or both
was associated with significantly higher reduction of drinking and abstinence evaluated over
68 weeks. No combination had better efficacy in reducing drinking than naltrexone or
U
behavioral therapy alone in the presence of medical management. No significant effects were
found with acamprosate. Placebo pills had a positive effect in this study above that of
AN
behavioral therapy alone. While disulfiram has been widely used, there is no clear clinical
trial data supporting positive outcomes(130). Other classes of psychotropic medications have
been investigated but results are inconclusive(131). Limited data on use of selective
M
serotonergic medications showed these may help with treating comorbid psychiatric
conditions such as mood and anxiety disorders but not alcohol dependence directly. The
D
identification and treatment of frequent psychiatric comorbidities associated with alcohol

dependence is critical(132,133). Treatment-nave active alcoholics had a greater number of
TE
psychiatric symptoms than normal controls, but less than treated alcoholics with long-term
abstinence and highlights the importance of identifying subsyndromal psychopathology even
when alcohol dependence has been treated(134).
EP
Non-pharmacological treatments have also been widely used. Several psychosocial

interventions have shown significant behavioral change in patients with alcohol dependence
including cognitive behavioral therapy (CBT), alcohol behavior coupled therapy, 12-step
C
therapist facilitated treatments, and motivational interviewing and support the

recommendation of some type of drug counseling to assist patients in remission(135,136). A
AC
systematic review included 13 studies with psychosocial interventions in inducing or

maintaining abstinence from alcohol in patients with chronic liver disease. Combined CBT,
motivational enhancement therapy, and comprehensive medical care increased alcohol
abstinence and combined CBT plus medical management reduced recidivism(137). Mutual
help and self-help organizations such as Alcoholics Anonymous can be helpful for many
patients to provide support for recovery and facilitate the formation of new social connections
but are not considered formal treatment and have not been extensively studied as part of
randomized controlled trials(138).
18
ACCEPTED MANUSCRIPT
Tobacco: Several studies have shown that smoking tobacco, particularly cigarettes increased
the risk for developing both acute(139,140) and chronic pancreatitis(141143) and this
relative risk is dose-dependent. While cigarette smoking is often present in alcohol abuse,
studies showing smoking as an independent predictive factor are emerging(139,144146).
PT
Prospective studies evaluating the effects of smoking cessation on chronic pain are lacking,
but smoking was associated with the chronification of pain in other pain syndromes(147). As
for alcohol use the health risks of smoking, including acceleration of disease progression, still
RI
makes abstinence advisable. Unfortunately, chronic pain has been associated with greater
challenges in smoking cessation (148,149). More than 80% of patients with alcoholic chronic
pancreatitis are smokers and smoking potentiates alcohol toxicity in dose-dependent
SC
way(142). Cigarette smoking has been shown to accelerate the progression of alcoholic
pancreatitis, with appearance of calcifications, and diabetes and this effect was independent of
amount of alcohol consumption(150). The exact mechanisms by which tobacco metabolites
U
affect the pancreas are unknown. Substances from smoking which have been considered as
causal agents include tobacco-specific metabolites such as NNK and nitrosamines as well as
AN
nicotine specific metabolites such as NNN and DEN(142). One hypothesis is that nicotine
results in high levels of intracellular calcium release which causes cytotoxicity(151).
Pharmacological treatment: Logically, smoking cessation should be a strong recommendation
M
for patients with chronic pancreatitis. Although cessation of smoking has been shown to
reduce the risk of developing pancreatitis(152), no study has evaluated the effect of smoking
D
cessation on pain in patients with CP. Given that nicotine is addicting, several medications
can help with cravings such as bupropion, which can also be safely combined with nicotine
TE
replacement therapies if necessary. In a recent double blind parallel group, bupropion plus
naltrexone outperformed bupropion plus placebo in smoking abstinence at 7 weeks but not 6
months(153). Varenicline, a partial nicotine agonist, has been shown to enhance smoking
EP
abstinence through reduction of smoking compared to placebo(154). Varenicline together

with nicotine replacement therapy enhance early and medium-term smoking cessation but did
not outperform nicotine replacement in the longer-term(155). Varenicline can also help with
C
cravings and reduction in overall alcohol consumption in some(156) but not all(157) studies
and thus can be an option for patients with both alcohol and tobacco addiction. A recent
AC
systematic review supported the combination of bupropion and varenicline for greater
efficacy than varenicline monotherapy for smoking cessation(158). Clonidine and
nortriptyline are considered second line symptoms to reduce nicotine withdrawal as the results
are inconsistent. In a review of Cochrane reviews of pharmacotherapy for smoking cessation
through 2012, 267 studies involving 101,804 participants were identified(159). Nicotine
replacement, bupropion, varenicline, and cytisine, another partial nicotine receptor agonist,
had the greatest evidence for improving the chances of quitting.
Non-pharmacological treatment: Cognitive behavioral therapy (CBT) combined with
smoking cessation medications can be effective in smokers who are motivated to quit(160).
Mindfulness-based therapy may help with recovery from smoking relapse(161). Other
19
ACCEPTED MANUSCRIPT
behavioral interventions that have shown promise are self-help groups, hypnosis, and
motivational interviewing techniques delivered by trained behavioral specialists(162).
PT
Pramod Kumar Garg & Eva Szigethy
Q5. Do enzymes and antioxidants influence pain in CP?
RI
Pancreatic enzyme therapy with high protease content may be tried as an initial treatment for
pain relief in patients with CP. Furthermore; combination of antioxidants in sufficient
dosages should be included in the armamentarium of pain treatments (Quality assessment:
SC
moderate; Recommendation: strong; Agreement: weak)
U
Role of Pancreatic Enzyme Supplementation on Pain Relief in Chronic Pancreatitis
Pancreatic enzymes have been used for relief of pain in patients with chronic pancreatitis
AN
(CP). The pathophysiological basis of using pancreatic enzymes is related to a possible
negative feedback loop involving cholecystokinin that regulates pancreatic exocrine secretion
(163). Intraduodenal infusion of trypsin decreases pancreatic exocrine secretion through
M
suppression of cholecystokinin (CCK)(164,165), but other studies have not shown that such a
negative feedback mechanism operates. It is believed that nutrients stimulate release of
D
cholecystokinin releasing factor (CRF) from the duodenum upon physiological delivery of
chyme into the duodenum. The CRF releases cholecystokinin, which stimulates pancreatic
TE
secretion. Theoretically, the pancreatic enzymes degrade CRF thus limiting the release of
cholecystokinin and subsequently decrease pancreatic secretion completing a negative
feedback loop. A reduction in pancreatic enzymes in patients with CP therefore increases
EP
cholecystokinin release and pancreatic secretion. This may increase intraductal pressure in
patients with CP who have ductal obstruction due to calculi or stricture and contributes to
pain. Thus, the rationale of giving pancreatic enzymes for pain relief is that adequate enzymes
C
will degrade CRF, decrease cholecystokinin release and thus reduce pancreatic secretion.
There are many concerns with such a hypothesis. First, the negative feedback loop is not fully
AC
understood well or confirmed. Second, increased pancreatic secretion in patients with CP is

counterintuitive because there is significant functional impairment in them. Third, increased
intraductal pressure is but one of the mechanisms of pancreatic pain and not widely accepted.
Fourth, enzyme supplementation has not been conclusively shown to decrease pancreatic
secretion and reduce intraductal pressure as hypothesized.
Six randomized clinical trials (RCTs) have been reported on the effect of pancreatic enzymes
in pain relief. In a review of these(166), pain relief using pancreatic enzymes as tablets was
noted in two trials(167,168) and no benefit was noted in 4 trials that used acid-protected
capsule forms of enzyme replacement(169172). The reason could be that the acid-protected
form of pancreatic enzymes was not released in the duodenum and, therefore, could not
20
ACCEPTED MANUSCRIPT
activate the proposed negative feedback mechanism. Pancreatic enzyme supplements have
shown most benefit for patients with small pancreatic duct disease, idiopathic pancreatitis and
among women. These trials were conducted in 1980s and 1990s and have had certain
methodological issues such as small sample size, heterogeneous patient population, variability
PT
in enzyme preparations, differences in outcome measures, and lack of standardized pain
measuring tools. Despite these concerns, pancreatic enzymes are widely prescribed to patients
with CP in the hope that at least some benefit may be derived. If enzyme therapy is tried in
RI
clinical practice as an initial treatment modality, the preparations of pancreatic enzymes
should be uncoated, contain large amounts of proteases (>25,000 USP units per tablet) and be
given in a dosage of four to eight tablets four times a day. In addition to the negative feedback
SC
regulation of pancreatic secretion, the other putative benefits of enzymes are (i) better
digestion of food leading to physiological ileal brake and help to regain intestinal motility as
the ileal brake is a regulatory physiological feedback mediated by delivery of nutrients into
U
the distal ileum, which inhibits gastric emptying and proximal small intestinal
motility(173,174). Ileal brake is mediated by peptide YY via vagal pathway(175). It has been
AN
shown that patients with CP particularly those with exocrine insufficiency have abnormal
digestive and interdigestive antroduodenal motility, which is corrected by pancreatic enzyme
supplementation(176). Alteration of ileal brake with abnormal intestinal motility may lead to
M
abdominal pain, discomfort, postprandial bloating and fullness. These symptoms may be
relieved by enzyme supplementation. (ii) Treat sub-clinical maldigestion and thus help regain
D
weight. (iii) contribute to a better glycemic control in those with diabetes. Further studies are
warranted to demonstrate any beneficial effect of pancreatic enzymes for pain relief taking
TE
into account variables such as the etiology of CP, stage of the disease, and preparation and
dosage of enzymes.
EP
Antioxidants may also be helpful in pain treatment. Normally, cells are in a state of redox
homeostasis that means that the free radicals (FR) or reactive oxygen species (ROS) generated
C
during the respiratory cycle are scavenged by the antioxidants. Oxidative stress (OS) refers to
an imbalance between pro-oxidants and antioxidants with increased free radical
AC
formation(177). Either an increased production of ROS or a deficient antioxidant capacity of

the cell may lead to OS. Increased FR production may occur due to exogenous sources such
as pollutants, xenobiotics, smoking etc. or endogenously through respiratory burst. Mild
oxidative stress is countered by cellular responses. If, however, ROS production is increased
excessively, the antioxidant capacity may be overwhelmed resulting in OS. Pathological
effects of ROS include lipid peroxidation, alteration in redox-sensitive signaling pathways,
inflammation, and cell injury. Severe oxidative stress can even cause cell death.
OS as a mechanism of inflammation in CP has been shown for the past 30 years. Many
studies have shown increased OS and deficient antioxidant capacity in patients with CP(178
182). Consequent to the understanding that OS might be related to chronic inflammation in
21
ACCEPTED MANUSCRIPT
patients with CP who have an inadequate antioxidant status, antioxidant supplementation has
been used to ameliorate OS and relieve pain in patients with CP.
A study from Manchester, UK was the pioneer study. Uden et al(183) used a combination of
dietary antioxidants (600 g organic selenium, 9000 IU -carotene, 0.54 g vitamin C, 270 IU
PT
vitamin E and 2 g methionine) and showed significant pain relief in patients with recurrent
acute and chronic pancreatitis. In an observational study, Whiteley et al.(184) studied the
effect of micronutrient supplementation in 103 patients with CP and showed that 75 patients
RI
remained pain free during a follow-up period of 9 years. There have been a total of 10 RCTs
on the role of antioxidants in patients with CP. In a study of 36 patients by Kirk et al(185),
significant improvement in the quality of life and pain was observed. A large, randomized,
SC
placebo-controlled trial showed that pain was significantly reduced during 6-month therapy
and the benefit was evident as early as 3 months(186). A recent RCT had shown that
antioxidants were ineffective in patients with predominantly alcohol induced CP(187).
U
However, several shortcomings of the study such as improper patient selection, continued
alcohol intake and smoking, opiate dependence, failed endoscopic/surgical therapy etc.
AN
limited the generalizability of the study(188,189). Recent meta-analyses have shown
beneficial effect of antioxidants in patients with CP(30,190). Another systematic review and
meta-analysis showed that antioxidants may help ameliorate pain in patients with CP(191).
M
This analysis included 9 RCTs with 390 patients were included. A combination of
antioxidants (selenium, -carotene, vitamin C, vitamin E, and methionine) showed significant
D
pain relief while studies with single antioxidant therapy showed no significant pain relief. The
latest RCT has shown that a combination of pregabalin and antioxidants for 2 months
TE
followed by only antioxidants for 4 months resulted in significant pain relief in patients
with CP who had recurrence of pain after ductal clearance by endotherapy or surgery(192).
Finally, a recent observational study has shown that long-term pain relief may be obtained
EP
with optimized medical therapy including antioxidants in patients with CP(193). Overall,
except for one RCT(187), all studies have shown significant pain relief with a combination
of antioxidants in patients with CP.
C
AC
22
ACCEPTED MANUSCRIPT
Asbjrn Mohr Drewes, Sren Schou Olesen & Eva Szigethy
Q6. Which analgesics are recommended for pain in chronic pancreatitis?

Currently the standard guideline for analgesic therapy in CP follows the principles of the
PT
pain relief ladder provided by the World Health Organization (WHO) adjusted to the pain
characteristics of this condition (Quality assessment: moderate; Recommendation: strong;
Agreement: strong)
RI
The individual experience and manifestation of pain is influenced by a complex series of
interactions involving sensory, pathophysiological, affective, socio-cultural, behavioural and
SC
cognitive elements(194). Hence, there is always more to analgesia than analgesics, but
pharmacological treatment is still the mainstay of pain treatment in CP(195). Of note, the
absorption of drugs can potentially be difficult to predict due to e.g., changes in the intestinal
U
pH, ischemia and bacterial overgrowth in patients with CP. Until now only one study has
studied these patients. Despite a normal absorption of pregabalin was found there is an unmet
AN
need for further studies in more complicated molecules(196). Pharmacokinetics can also be
changed in patients having problems with intake of tablets, and patch formulations with slow
absorption of analgesics may be considered.
M
Currently the standard guidelines for analgesic therapy in CP follow the principles of the
pain relief ladder provided by the World Health Organization (WHO). This principle, which
D
was originally launched for cancer pain treatment, is based on the serial introduction of drugs
with increasing analgesic potency. This approach enables a simple stepwise escalation of
TE
drugs with increasing analgesic potency (level I-III) until pain relief is obtained, with
simultaneous monitoring and handling of side effects (figure 1)(197). In the following the
analgesics most used are described, and where possible special studies and precautions for CP
EP
are highlighted:
C
AC
Figure 1: Modified version of the WHO analgesic pain ladder. At level 1 treatment with non-opioids such as
paracetamol and non-steroidal anti-inflammatory drugs will be initiated with or without adjuvants. If pain
increases or persists level 2 treatment will be initiated. Level 2 treatment include opioids for mild or
moderate pain with or without adjuvants. If pain still persists or increases, level 3 treatment may be initiated.
Level 3 treatment includes opioids for moderate or severe pain with or without non-opioids and/or adjuvants.
23
ACCEPTED MANUSCRIPT
Simple analgesics are used as a cornerstone in pain treatment and paracetamol is the preferred
level I drug due to its limited side effects. It must be used with caution in patients with
concomitant liver impairment or severe malnutrition, but otherwise there are no major
restrictions. The non-steroidal anti-inflammatory drugs (NSAIDs) should in general be
PT
avoided due to their gastrointestinal toxicity (198). This may especially be relevant in CP as
patients are already predisposed to peptic ulcer and have decreased duodenal pH due to
insufficient buffering with bicarbonate(199). Nonetheless, NSAIDs are very effective in
RI
selected patients and may be used for short-term treatments (weeks). The variability in
gastrointestinal and cardiac toxicity should be taken into consideration and proton pump
inhibitors are normally co-prescribed. In clinical practice level 1 analgesic`s are often
SC
insufficient to alleviate pain as monotherapy, but it is important to maintain their use when
more potent analgesics are considered.
U
Adjuvant analgesics are a heterogeneous group of drugs initially developed for indications
other than pain and include antidepressants, anticonvulsants including the gabapentoids as
AN
well as anxiolytics. Although adjuvant analgesics have been widely used in the clinic to treat
pain in CP, only the gabapentoid, pregabalin, has been investigated in a placebo controlled
randomized trial titrated to 300-600 mg BID. In the short-term, it was found to induce a
M
moderate pain relief with relatively limited side effects when used as an adjuvant analgesic in
combination with the patients usual analgesic medication (200). Further, a reduction in opioid
D
dose in the short-term may be seen although longer-term studies are needed(201).
TE
Anti-depressive drugs are widely used for pain treatment and although no data exist in CP,
their positive effect in patients with neuropathic pain (thought to be prevalent in CP) makes
them attractive(202). Tricyclic antidepressants (TCA), selective serotonin reuptake Inhibitors
EP
(SSRI) and serotoninnorepinephrine reuptake inhibitors (SNRI) have been used successfully
in functional gastrointestinal disorders. It is, however, unclear if they all have direct analgesic
effects versus indirect benefit by reducing anxiety and depression(203). On the other hand,
TCAs appear to have analgesic and neuromodulatory properties that are unrelated to their
C
psychotropic effects(204,205). It is important to start at very low doses and titrate slowly over
AC
weeks as side effects such as cardiovascular can be dose-limiting(206). It should be noted that
there are major differences in receptor properties and analgesic mechanisms between the
different TCA and SSRI/SNRIs and therefore an individual approach is necessary. Due to the
sedative effects a single dose at night-time may be preferable. Unfortunately, clinical
experience indicates that the side effect profile often makes them less suitable in patients with
CP. For further reading, see Trnblom et al. 2015(207) and Scottish Intercollegiate Guidelines
Network(207).
Opioid analgesics are indispensable for the management of pain(208), but therapy should
only be initiated when more simple strategies have failed following a reasonable trial
24
ACCEPTED MANUSCRIPT
period(209). Opioids are highly effective and safe analgesics and their appropriate use by
competent clinicians is a crucial element in modern pain management. However, treatment is
often complicated by severe adverse effects and may lead to addiction. Furthermore, some
opioids like codeine, tramadol and morphine are contraindicated or require prolonged dose
PT
intervals in patients with severe renal and hepatic insufficiency, which is not uncommon in
CP. While not studied in CP, patients who have chronic pain and opioid use disorders may
benefit from partial opioid antagonists such as buprenorphine, though randomized controlled
RI
trials are not available(210,211). Opioids should not be used in isolation, but form part of a
multi-faceted strategy that includes all necessary adjuvant analgesics, non-drug interventions,
psychological support and rehabilitation. There are enormous variations in opioid use across
SC
the globe, and even within close regions major variations are observed(212). This is based
partly on local traditions, partly on regulatory matters and to some degree by opiophobia
and will not be the discussed further in this section. As opioid use seems to be a necessary
U
step to dampen pain in many patients with CP it is mandatory that pancreatologists understand
the complexity of opioid treatment, or alternatively treat patients in close collaboration with
AN
dedicated pain specialists. Of note, all patients must be fully educated on the proposed
therapeutic strategy and informed about the risks for addiction and side effects especially
opioid induced bowel dysfunction, emesis and affection of the central nervous system. In
M
some cases the pain increases despite increased dose and in such situations opioid induced
bowel dysfunction or opioid induced hyperalgesia (narcotic bowel syndrome) should be
D
suspected as it may mimic the pain in CP. For details, see Drewes et al. 2016 and Drossman
and Szigethy 2014(213,214). Treatment may include increased use of laxatives, opioid
TE
antagonists with restricted effect on the gut, tapentadol or in case of hyperalgesia tapering of
opioids(214,215). Patients on long-term opioid therapy must be kept under close clinical
surveillance and it shall be stressed that only about 25% of patients benefit from treatment.
EP
After 6 months of opioid therapy, a dose reduction (or drug holiday) should be considered
and discussed with the patients(212,216). For further information the reader is referred to e.g.
Dowell et al. 2016)(216)
C
Codeine is a weak opioid in level II analgesia, but it is metabolized to morphine and therefore
associated with the same spectrum of opioid-related side effects as seen for stronger opioids.
AC
Tramadol possesses both a weak opioid agonist activity along with an effect on noradrenaline
and serotonin uptake(217). Tramadol is often the preferred level II analgesia and was shown
to be superior to morphine in patients with CP, with fewer gastrointestinal side effects for the
same level of analgesia (218). Level III analgesia comprises the group of strong opioids such
as morphine, which are widely used for pain in CP. Most clinical available opioids have their
activity at the -receptor, but preclinical and experimental studies suggest that activation of
the -receptor (another opioid receptor activated by e.g. oxycodone) may also be important in
visceral pain including pain in CP(110,219,220). Hence, oxycodone may posses an advantage
over conventional opioids for pain treatment in CP, but head-to-head comparisons in clinical
studies with long-term follow-up are not yet available. Transdermal administration (plaster
25
ACCEPTED MANUSCRIPT
formulation) of opioids is not recommended as first line opioid therapy for CP, but should be
reserved to patients having trouble with tablet ingestion. Hence, in an open label randomized
crossover trial, transdermal fentanyl plaster was compared to sustained release morphine
tablets. No significant differences were found for pain control or patients preference or
PT
quality of life, while 44% of patients treated with fentanyl plaster reported side effects mainly
as a rash at application site (221)
There is marked inter-individual variability in responsiveness to different opioids, and in
RI
circumstances where an individual patient fails to achieve satisfactory pain control and/or
they are troubled by unacceptable side effects, a trial of an alternative opioid is indicated.
Opioid rotation may be difficult and for guidelines the reader is referred to(212). In patients
SC
with a severe and debilitating pain pattern, a more aggressive top-down approach using
opioids combined with adjuvant analgesics as first line therapy may be recommended to
control pain(217).
U
In some patients unconventional treatment with drugs such as ketamine is beneficial.
AN
Ketamine, an N-methyl-D-aspartate receptor antagonist, is used not only for anaesthesia, but
also as a potent analgesic in acute and chronic pain as well as an antihyperalgesic used to
reduce central sensitization(222). Multiple studies have consistently produced positive results
M
regarding the use of ketamine in chronic pain patients with central sensitization and
hyperalgesia and it thus comprises an interesting remedy to revert reduce central sensitization
D
and its associated hyperalgesia in CP. This was supported by a double-blinded crossover trial
designed to evaluate the effect of ketamine infusion on experimental hyperalgesia associated
TE
with CP(109). However, there are several limitations with the drug due to the side effects,
which may be rather severe with longer-term negative consequences, and a current
prospective clinical trial is awaited to establish its role in the management of painful CP(223).
EP
Experimental and clinical evidence suggest a key role for nerve growth factor (NGF) in the
generation and maintenance of a wide range of pain states. Consequently, drug discovery
efforts have resulted in several humanized anti-NGF monoclonal antibodies that have entered
C
clinical trials as potential analgesics(224). NGF is up-regulated in patients with CP and is

known to play a pivotal role in the process of peripheral sensitization. Therefore NGF-
AC
antagonism may also be effective for pain relief in these patients and in other visceral pain
syndromes where up-regulation of NGF is assumed to mediate pain(225).
Somastotatin-analogue inhibits pancreatic secretion by blocking CCK and secretin release and
also by a direct inhibitory effect on acinar cells. These effects may theoretically alleviate pain
through reduction of pancreatic ductal pressure and by lowering the central effects of CCK.
There are conflicting data about the efficacy of somastotatin-analogues for pain in CP. While
early pilot series of octreotide showed an effect on pain control, this effect could not be
confirmed in later randomized controlled trials(226). Other drugs such as for example
clonidine (centrally acting 2 adrenergic agonist), quetiepine (second generation
antipsychotic) and neurokinin-1 receptor (NK-1R) antagonists have all demonstrated
26
ACCEPTED MANUSCRIPT
analgesic efficacy and may be used in selected patients(227). It may also be indicated to use
benzodiazepines, anti-psychotics or cannabinoids in difficult cases although it should be
stressed that no data in CP are not yet available to document their use.
PT
Indication for treatment
RI
(pain pattern, sufficient intensity)
SC
Primary pancreatic pain Secondary causes for pain, e.g.
peptic ulcer
Malnutrition, red flags Suspected stones Autonomic pancreatic Treat appropiately

for lifestyle and strictures pain
U + Consider non-coated
Optimise nutrition, advise Consider endoscopy and enzymes or antioxidants
-
against smoking and alcohol etc.
AN
ESWL
- - +
Start treatment with PCM or + Follow the
+ NSAID in selected cases patient
-
M
TCA
SSRI
+ Psychological evaluation suspect
component of mood disorder
SNRI
+ -
D
Follow the - Neurophysiological evaluation

+ Gabapentinoids
patient suggest segmental hyperalgesia
TE
Considerer cognive
therapy etc.
+
- Follow the
patient
+
EP
Neurophysiological evaluation suggest

SNRI or TCA
deficient descending inhibition
-
C
Start treatment with weak opioids

such as tramadol and codeine
+ -
AC
Follow the
patient
Consider strong opioids

+ Follow the
patient
-
Alternative non- Opioid rotation, new Consider OIBD and Consider surgery or
pharmacological combination therapies, narcotic bowel. splanchnicectomy
treatment such as alternative Taper opioids or
acupuncture, transcranial pharmacological increase laxative
magnetic stimulation ond treatment such as treatment
spinal cord stimulation ketamine,
antipsychotics,
clonidine etc.
Figure 2: Suggested algorithm for pharmacological treatment (grey boxes) of pain in chronic pancreatitis. 27
ACCEPTED
Autonomic pain is defined as a primary MANUSCRIPT
pain type that is not related to local complications such as
pseudocysts or obvious duct strictures and stones. In most cases, combination therapies are necessary.
Treatment with antidepressives is guided by psychological evaluation including assessment of
catastrophizing, depression etc. In case gabapentinoids are considered we use evaluation of the ration
between segmental and generalised hyperalgesia (see text). Of note, treatment with gabapentinoids, TCA,
SNRI (or SSRI in selected cases) should be titrated slowly until sufficient effect or intolerable adverse effects
occur. Treatment shall be individualised due to major differences in receptor properties and analgesic
mechanisms between patients. NSAIDs are normally not indicated and should be used carefully. Opioids
shall be avoided if possible due to the major side effects on the gastrointestinal tract etc., but in severe pain
they may be prescribed for limited periods and the physician shall always be aware of opioid induced bowel
dysfunction and hyperalgesia (narcotic bowel). The timing of surgery is up to discussion (please see Q11)
PT
and is placed in the bottom of this algorithm mainly dealing with medical therapy.
Plus sign indicate sufficient/satisfactory effect.
Minus sign indicate insufficient effect
RI
ESWL: extracorporal shock wave lithotrypsy
PCM: paracetamol
NSAID: non-steroidal anti-inflammatory drugs
TCA: tricyclic antidepressives
SC
SNRI: serotonin-noradrenalin reuptake inhibitors
SSRI: selective serotonin reuptake inhibitors
OIBD: opioid induced bowel dysfunction
U
AN
In practice pain treatment is mainly guided by evidence from somatic pain studies together
with individual experience and traditions. However, the variability in phenotypic presentation
of different pain syndromes is found to be greater between patients than between different
M
pain syndromes, indicating that mechanistic etiologies are based on the individual rather than
the level of disease (228). In figure 2 an example of a treatment algorithm used at Centre for
D
Pancreatic Diseases, Aalborg University Hospital, Denmark is shown. A multidisciplinary

approach is suggested both for evaluation and treatment of patients. This includes
TE
neurophysiological and psychological testing whereby specific pain mechanisms and

psychiatric comorbidity are detected and rational treatment can be initiated. For example
segmental hyperalgesia of the epigastric skin area (pancreatic viscerotome), detected by
EP
quantitative sensory testing, may serve as a clinical marker of central sensitization and predict
the response to gabapentinoids(107). The tests are partly described in Q3 where more
references can be found. Also, up to 40% of chronic pain patients are depressed and
C
identification of mood disorders may identify patients where adjuvant therapy with
antidepressants are particular beneficial (see section about psychological treatment). In
AC
addition, it is of outmost importance to identify secondary causes for pain (e.g. peptic ulcers
or pseudocysts) as these are often easy to diagnose and treat, and secondary causes of pain
should always be considered when the patient is experiencing an exacerbation in pain
symptoms. The multidisciplinary approach to pain in CP, although typically used in centers
dedicated for pancreatic pain therapy, may also be used in less specialized settings to guide
pharmacotherapy in difficult cases.
Over the past few decades, significant progress has been made in our understanding of the
basic science of pain and the effect of analgesics. Non-invasive human methods using
methods such as quantitative sensory testing, immunohistochemistry, neurophysiological
evaluation, and assessment of brain function with electrophysiological methods and imaging
28
ACCEPTED MANUSCRIPT
have provided greater insights into the mechanisms of pain in CP and may lead to the
development of more specific and effective therapies that may be individualized to fit the
characteristics of the individual patient(217,229). Until then we are left with the guidelines
outlined above. However, treatment should always be individualized and preferably initiated
PT
and monitored by expert pancreatologists due to the complexity of pain and complications to
CP that always needs to be considered and treated appropriately.
RI
U SC
AN
M
D
TE
C EP
AC
29
ACCEPTED MANUSCRIPT
Myriam Delhaye, Shuiji Isaji and Stefan A W Bouwense
Q7. Is endoscopical therapy effective for pain treatment in CP?

The best candidates for successful treatment of painful CP with first-line endoscopical
PT
therapy are middle-aged patients with distal obstruction of the main pancreatic duct (single
stone and/or single stricture in the head of the pancreas) and in the early stage of the disease,
that means as soon as possible after the first pain attack. Endoscopical therapy can be
RI
combined with Extracorporeal Shock Wave Lithotripsy (ESWL) in the presence of large (> 4
mm) obstructive stone(s) located in the pancreatic head, and with ductal stenting in the
presence of a single main pancreatic duct stricture that induces a markedly dilated duct.
SC
(Quality assessment: moderate; Recommendation: strong; Agreement: conditional)
Endoscopical therapy (ET) in painful chronic pancreatitis (CP) is based on the rationale that
U
pain is related to an outflow obstruction of the main pancreatic duct (MPD) due to stricture(s)
or pancreatic intraductal stone(s).
AN
Therefore ET is indicated for selected patients with both:
1. persistent (continuous or recurrent) pain related to CP after failed conservative pain
management;
M
2. outflow obstruction of the MPD (i.e. MPD dilatation 5 mm), secondary to ductal
stricture(s) and/or stone(s) amenable to ET.
D
Retrospective/observational studies: According to a multicenter study of > 1,000 patients who

had been selected for ET of painful CP, MPD obstruction was caused by pancreatic stone(s)
TE
alone, ductal stricture(s) alone and a combination of stone(s) and stricture(s) in 18%, 47%,
and 32% of cases respectively(230).
ERCP can achieve MPD drainage by pancreatic sphincterotomy of the major and/or minor
EP
papilla, by temporarily stent insertion in the case of dominant stricture in the head of the
pancreas, or by pancreatic stone extraction, usually after fragmentation with ESWL.
The effectiveness of ET is usually the result of these combined procedures, all of these aimed
C
to restore drainage of the MPD. With this approach 79% - 85% of patients experienced
complete or partial pain relief in the short-term (follow-up (FU) < 2 years) (Tables 1 and 1S,
AC
all Tables appear after Q8), 76% - 94% in the medium-term (FU 2 5 years) (Tables 2 and
2S) and 66% - 96% in the long-term (FU > 5 years) (Tables 3 and 3S).
Endoscopic MPD drainage yielded similar results in the different categories of patients
(stone(s) alone, ductal stricture(s) alone and both stone(s) and stricture(s)), with 51% (523 /
1018) of patients having no pain at all at a mean FU of 4.9 years (intention-to-treat
analysis)(230).
Several independent series from different parts of the world have reported the long-term
outcome (FU 24 months) after endoscopic therapy ( ESWL for 60% of patients) in a
total of 1657 patients (Tables 4 and 4s). Complete or partial pain relief was reported on an
30
ACCEPTED MANUSCRIPT
average in 78% (43% - 85%) of patients and surgery was avoided in 80% (74% - 96%) of
patients (1265 / 1580) in studies where this data was available (Tables 4 and 4S).
These studies are relatively homogeneous regarding baseline characteristics of included
patients (mostly middle-aged men with pain, recurrent or continuous, alcohol abuse as main
PT
etiology of CP, average duration of disease prior to ET around 3 5 years, severe CP with
endocrine / exocrine insufficiency at baseline around 30%) (Tables 1 to 4).
However, the quality of evidence of reported results remains low in most of these
RI
retrospective observational non-randomized studies, with heterogeneity mainly in the use of
unstandardized pain relief assessment, in the duration of follow-up and in the sample size,
with no comparative analysis with a control group. Moreover, the retrospective design of a
SC
study may overestimate the treatment success rate.
Randomized studies: Only two randomized controlled trial (RCT) were included in two
Cochrane reviews published in 2012 and 2015(231) comparing ET and surgery. They
U
included in the ET arm, only 19 patients for the highest quality RCT(232) and 36 patients in
the other one(233).
AN
In the first RCT(232), in addition to the very small sample size of the study, the overall
technical success rate of ET was only 53% (maybe because ESWL and ET were not
performed by the same team in the same hospital, maybe because duration of pancreatic duct
M
stenting was limited to a 27 weeks duration) as compared to 80% (1638 / 2040) (52% - 100%)
in 8 studies with comparable patients (Table 2).
D
Pain relief assessment, based on 6 measures of the Izbicki pain score during the first 2 years
after ET was reported as complete or partial in only 32% of patients (6/19).
TE
In the second RCT(233), the ET was suboptimal also as ESWL and repeated ET in case of
recurrent pain were not applied. Indeed, recurrent pain attacks after ET occurred in
approximately one third of patients, and was usually related to stone migration or recurrence,
EP
progressive stricturing of the MPD or pancreatic stent obstruction or dislodgment(234). All

these situations could be further managed successfully by endoscopy ESWL with a similar
response rate as that for initial therapy(235). Contrary to surgery, patients age as well as
C
severe co-morbidities occurring in CP such as portal hypertension are not risk factors for ET-
related morbidity and mortality. Indeed, advanced age, severe co-morbidities, portal
AC
hypertension with vascular collaterals is relative or absolute contraindications for this type of
surgery.
Therefore, patients included in the ET group in both RCT were likely to have a poor outcome
because the technical success of ET was poor(232) and the optimal ET was not
performed(232,233)(233).
Stenting: In 6 retrospective case series(236241) with FU 24 months, including a total of
450 patients, pain improvement was reported in 67% (301 / 450, ranging from 43% to 74% in
intention-to-treat analysis) after single plastic stent removal.
In the largest study(239) after a median stenting duration of 23 months, 62% of patients
maintained satisfactory pain control without pancreatic stent replacement during a median
31
ACCEPTED MANUSCRIPT
time of 27 months. The majority of pain recurrences, requiring a new period of pancreatic
stenting occurred during the first year following stent removal (79%) with almost all (97%)
having relapsed by 24 months. Consequently, if a patient remains stable during the first year
after stent removal, subsequent relapse and need for re-stenting are less likely.
PT
Results of multiple plastic stenting were reported in a single study that included 19
patients(242). A median number of 3 simultaneous stents were left in place during 7 months.
At a mean FU of 38 months following stents removal, 84% (16/19) of the patients remained
RI
free of pain.
For refractory MPD stricture, the temporary insertion of fully-covered self-expandable
metallic stent (FC-SEMS) could be an option (Table 5). While uncovered and partially
SC
covered SEMS have provided disappointing results(243), 4 recent studies(244247) have
reported pain improvement in 53/61 patients (87%) but with a short FU after stent removal.
Interestingly, a recent systematic review suggested that FC SEMS provide similar good
U
results as multiple plastic stents(248).
Factors predicting favorable clinical outcome after ET ESWL have been identified:
AN
1. Immediate pain relief or improvement after ET was significantly associated with technical
success (successful decompression of the MPD as suggested by a decrease in MPD
diameter or a complete / partial duct clearance) and a low frequency of pain attacks before
M
ET(249252) (Table 1).

2. Medium-term clinical improvement correlated with low-frequency of pain attacks before
D
treatment (Type A pain pattern according to Ammann RW et al(8)), short duration of

disease before treatment, and absence of MPD stricture(236,251,253,254) (Tables 2 and
TE
4). Note that in the RCT from Cahen et al(232), Type A pain pattern was recorded in only
37% of the patients randomized in the ET group and 16/19 (84%) presented with a MPD
stricture.
EP
3. Long-term clinical success was associated with a short duration of disease before
treatment, absence of ongoing smoking at the end of FU, a shorter duration of ET and a
lower number of ERCP procedures(255,256). Other prognostic factors for pain relapse
C
during FU were identified in the study by Tadenuma et al(234), i.e. incomplete MPD
stones removal after ET and the presence of MPD stricture (Table 3).
AC
Taking into account all these above data, an algorithm is suggested for selection of good
candidates for first-line limited trial of ET ESWL (Figure 3). If clinical success could be
obtained with 5 endoscopic interventions, the patient will probably achieve long-term
favorable outcome. The cut-off of 5 intervention is based on a study by Ali et al (257) They
found that more pain relief after surgery was observed in patients who had 5 or fewer
endoscopic treatments prior to surgery with an OR of 2.5 (95% CI, 1.1-6.3; p=0.04)). In this
study, the multivariable analysis identified 3 independent risk factors for pain relief after
surgery. These were pain duration of 3 years or less, no preoperative use of opioids and 5 or
less endoscopic procedures prior to surgery. The authors tested also the cut-off of 3
endoscopic treatments with a statistically significant difference in the univariate analysis, but
32
ACCEPTED MANUSCRIPT
only the cut-off of 5 remained significant in the multivariate analysis. They proposed that the
success of endoscopy should be determined in 5 or less endoscopic interventions to optimize
outcome of future surgery. If endoscopy does not provide persistent pain relief, then surgery
should be considered. Otherwise as observed in 18% of long-term followed patients after ET
+ ESWL(255), other factors than increased pancreatic ductal pressure could be involved in the
PT
pain syndrome and, for these patients, no further attempts at drainage should be proposed.
RI
U SC
AN
M
D
TE
C EP
Figure 3: The first step for the management of pain in patients with chronic pancreatitis should be to make a
AC
correct diagnosis based on clinical history and imaging procedures, and to exclude alternative diseases or
complications that could induce pain not related to pancreatic ductal obstruction by stones and/or strictures.
The second step should be to select the appropriate candidates for endoscopy (see the text for the definition
of best candidates for endoscopical treatment with or without ESWL) and to treat such good candidates early
in the disease course (within the first 2 to 3 years after symptom onset), with a limited number (< or = 5) of
endoscopic interventions. If no persistent pain relief was obtained after a limited trial of endoscopic
treatments +/- ESWL, that means that other factors than increased pancreatic ductal pressure could be
involved in the pain syndrome and for these patients no further attempts at drainage should be proposed. In
these patients or if the patient is not a candidate for endoscopy or in case of technical failure of endoscopy,
medical treatment could be tried. Surgery and alternative options could also be proposed if no persistent pain
relief was obtained after endoscopy, in case of limited effect of medical treatment.
33
ACCEPTED MANUSCRIPT
PT
RI
SC
Christopher Halloran, Myriam Delhaye
Q8. Is ESWL effective for pain treatment in CP?
U
In patients with uncomplicated painful calcified CP, ESWL alone is a safe and effective
treatment. Best candidates for benefiting from initial first-line ESWL are patients with
AN
obstructive calcifications, > 4 mm confined to the head of pancreas. Combining systematic
endoscopical therapy with ESWL adds to the cost of patient care, at the same time not
probably improving the outcome of pancreatic pain (Quality assessment: moderate,
M
Recommendation strong; Agreement: conditional).

D
ESWL for pancreatic stones is indicated for patients with all of the following:
1. recurrent attacks of pancreatic pain;
TE
2. marked changes in the pancreatic ductal system i.e. dilated main pancreatic duct
3. obstructing ductal stones (minimal diameter: 2 5 mm, calcified or radiolucent)(258)
Regardless of the method of shock waves generation (electrohydraulic, electromagnetic,
EP
piezoelectric) ESWL provides high rates of stones fragmentation (average of 91% ranging
from 54 to 100%)(258).
ESWL was proven useful for treating chronic pancreatitis (CP) related pain in a meta-
C
analysis(259) that included a total of 588 patients from 16 studies. It was concluded from this
analysis that ESWL effectively relieves MPD obstruction and alleviates pain in chronic
AC
calcifying pancreatitis most often in combination with endoscopic therapy (ET). The mean
effect size (weighted correlation coefficient) on pain at follow-up (FU) was 0.62 0.7, with
homogeneity reported for effect size between series.
A most recent meta-analysis regarding the success of ESWL in chronic calcific pancreatitis
management reviewed data from 27 studies including 3189 patients(260).
The pooled proportion of patients with absence of pain at FU was 53% (95%, CI 51 55) and
mild to moderate pain at FU was 33% (95%, CI 31 36).
Narcotic use was decreased in 80% (95% CI, 77 82) of the pooled proportion of patients.
Surgery was required in 4.4% (95% CI, 4 5) of the pooled proportion for various reasons,
mainly for inadequate pain control with ESWL. Limitations of this meta-analysis are
34
ACCEPTED MANUSCRIPT
acknowledged i.e. the varying etiologies of CP, the wide range of FU periods among various
studies, the ESWL equipment varied among the studies, the pain score not universal and
mainly the absence of control arm in all studies.
In a prospective randomized study that compared ESWL alone with ESWL combined with
PT
endoscopy(261), including 55 patients with uncomplicated painful CP (no pseudocyst, no bile
duct stricture) and calcifications > 4 mm obstructing the MPD, there was no evidence that the
combination of endoscopy and ESWL was better than ESWL alone for the prevention of pain.
RI
Indeed ESWL alone (n=26) provided similar results than ESWL plus ET (n=29) in terms of
decreasing number of pain episodes after trial intervention compared to baseline. Moreover,
complete pain relief, 2 years after treatment, was achieved in 62% and 55%, respectively
SC
(p=NS).
ESWL alone was also reported as a first-line treatment of calcified pancreatic stones in three
non-randomized Japanese studies(262264) (Table 6). Interestingly, the proportion of patients
U
treated by ESWL alone in one large study was 57% (318 / 555)(263).
Among 552 patients who underwent ESWL alone and included in these three studies,
AN
complete spontaneous MPD clearance was obtained in 63% (345 / 552, range 49% - 75%). In
the study by Inui et al(263) the spontaneous ductal clearance after ESWL alone was not
significantly different from that observed in the whole series (70% vs 73%). On the other
M
hand, the ductal clearance rates were 49% after ESWL alone and 74% after ESWL ET in
the study by Suzuki et al(264).
D
Factors associated with complete stone clearance included the presence of a single stone vs.
multiple stones(234,265) the absence of a MPD stricture(234) and a lower density of stones
TE
(< 820 Hounsfield units)(266).

In the study by Ohara et al(262), a high rate of complete or partial pain relief (24/32, 75%)
was obtained after ESWL alone over a mean FU of 44 months. This could be explained by the
EP
selection of patients without severe MPD stricture (in 22 out of 32 patients) and with good
residual exocrine pancreatic function (only 2 patients (6%) presented steatorrhea) in this
study.
C
After treatment with ESWL (alone or combined with endoscopic drainage), most of the
patients who experienced pain relapses developed them during the first two years following
AC
treatment(251,255,261). Interestingly, after treatment with ESWL alone, need for ERCP for
pain relapses has been reported in only 3/32 (9%)(262) and in 8/26 (31%)(261) patients
during FU.
Pain relapse occurred significantly more frequently in patients with incomplete removal of
stones after the initial therapy (ET ESWL) (HR, 3.7; p=0.007) and in those with a MPD
stricture (HR, 3.4, p=0.02). Both factors were significant risk factors for pain relapse on
multivariate analysis(234).
Other factors independently associated with long-term ( 2 years) pain relief that could be
taken into consideration for the selection of the best candidates for ESWL ET are a short
disease duration prior to treatment, a low frequency of pain attacks before treatment, a
35
ACCEPTED MANUSCRIPT
complete ductal stone clearance, the absence of MPD stricture and discontinuation of alcohol
and tobacco during FU(234,240,251,255).
PT
RI
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
36
PT
Table 1 : ESWL + Endoscopy Short term FU < 2 y
RI
Author Design Population Intervention Outcome Comments
(year) (ref)
SC
Delhaye Prospective 123 patients: ESWL, EPS Pain relief
Recurrent pain
(1992)(249) observational 81% Pancreating assessment
men, 80% OH more frequent
U
stenting: 39% Pain free interval
when no
Age: 44.8 y Technical success:
AN
90% Complete pain relief: decrease in MPD
Duration of 40/88
(111 / 123 MPD )
disease: 4.5 y Partial pain relief:
Complete MPD
M
Severe CP: 94% 35/88
clearance: 59%
Pain: 87% (72 / 123) Complete or partial
D
(Type A: 81%)
pain relief: 85%
FU: 14 m Surgery: 8%
TE
Diabetes: 35%
Steatorrhea: 28% LOE : moderate
EP
Schneider Retrospective 50 patients ESWL, EPS Pain relief
No predictive
(1994)(267) observational 78% men, 66% OH Pancreating assessment
factor of pain
stenting: 26% pain frequency
C
Age: 45 y relief
Technical success:
Duration of Complete pain relief:
AC
100%
disease: 4.8 y (50 / 50 complete or 24/39 = 62%
Severe CP: -- partial MPD clearance) Partial pain relief: 7/39
Pain: 100% Complete MPD = 18%
(Type A: 72%)
clearance: 60% Complete or partial
(30 / 50) pain relief: 79%
FU: 20 m
ACCEPTED MANUSCRIPT
37
PT
Diabetes: 38% Surgery: 12%
Steatorrhea: 14% LOE : low
RI
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
38
PT
Brand Prospective 48 patients EPS (n=48) Pain relief Improvement of pain
(2000)(252) observational 73% men, 64% OH ESWL (n=48) assessment score correlated
RI
Age: 51 y
Pancreating Izbicki pain score with in MPD (r =
stenting: 56% improved 0.37, p<0.05)
Duration of Improvement of pain
SC
Technical success: --
disease: 69 m (complete #: 60%; Complete pain relief: score associated
Severe CP: 92% complete MPD 17/38 = 45% with non-alcoholic
Pain: 98% Partial pain relief:
U
clearance: 44%) CP (RR 1.4, 95% CI 1.1 -
(Type A: 67%)
14/38 = 37% 1.8)
AN
FU: 7 m (n=38) Complete or partial
Diabetes: 33% pain relief: 82%
LOE : low
M
Steatorrhea: --
Karasawa Retrospective 24 patients ESWL alone (n=10) Pain relief No factor
D
(2002)(268) 79% men, 71% OH ESWL + Endoscopy assessment: NA identified for
(n=14) predicting
Age: 53 y
TE
Technical success: stone(s)
Duration of Immediate pain relief
79% disintegration
disease: 4.4 y (complete #: 19/24;
Complete: 19/20 =
EP
Severe CP: -- complete MPD 95%
Pain: 83% clearance: 13/24 = 54%)
C
(20/24)
FU: 12 m Sustained pain relief
AC
Diabetes: 50% at 12 m
Complete: 11/24 =
Steatorrhea: --
46% LOE : very low
Tandan Prospective 1006 patients ESWL (n = 1006) Pain relief

(2010)(269) EPS (n = 938) assessment
ACCEPTED MANUSCRIPT
39
PT
observational 66% men, 8% OH Pancreatic stenting VAS
(n = 542, 54%) analgesic use/m
Age: --
RI
Duration of
Duration of Complete pain relief:
pancreatic stenting:
disease: 1.7 y 326/846 = 39%
SC
6m
Severe CP: 100% Complete or partial
Technical success:
Pain: 100% pain relief: 711/846 =
93% (complete or LOE : moderate
FU: 6 m
U
partial ductal clearance) 84%
Diabetes: 32% Complete MPD Surgery: 38/846 =
AN
Steatorrhea: 7% clearance: 76% 4.5%
M
Milovic Prospective 32 patients ESWL (n=32) Pain relief Improvement of
D
(2011)(270) 75% men, 81% OH Pancreatic stenting: assessment pain score not
TE
19/32 (59%) 5-point Likert scale associated with
Age: 48 y
Technical success: pain score complete MPD
Duration of
100% clearance
Immediate pain relief:
EP
disease: -- (decompression of the
Severe CP: 100% MPD) 24/32 = 75%
Pain: 100% Complete MPD At 6-9 m after ET,
C
FU: 6-9 m clearance: 41% improvement in pain

Diabetes: --
AC
score: 28/32 = 88%

Steatorrhea: -- Complete pain relief: LOE: low
17/32 = 53%
Kawaguchi retrospective 66 patients ESWL: 41/66 = 62% Pain relief In patients with
(2013)(271) 86% men, 88% OH Pancreatic duct assessment: NA only stones
stenting: 51/66 =
ACCEPTED MANUSCRIPT
40
PT
Age: 59 y 77% Complete pain relief: Lower number of
Duration of Technical success: 60/66 = 91% procedures
RI
disease: - 61/66 = 92% Partial pain relief: 5/66 Fewer patients who
Severe CP: 100% = 7% required at least 1 y
Complete or partial
SC
Pain: 100% of treatment
FU: ND pain relief: 98%
Diabetes: -- LOE: very low
U
Steatorrhea: --
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
41
PT
Table 1S= ESWL + Endoscopy Short term FU < 2 y Studies 50 patients
Author (year) Design Number of Complete or partial FU Comments (LOE)
RI
(ref) patients pain relief (months)
Delhaye Prospective 123 85% (75 / 88) 14 Recurrent pain more
SC
(1992)(249) ITT: 75 / 123 = 61% frequent when no decrease
in MPD
U
LOE: moderate
AN
Schneider Retrospective 50 79% (31 / 39) 20 --
(1994)(267) ITT: 31 / 50 = 62%
M
LOE: low
Tandan Prospective 1006 84% (711 / 846) 6 --
D
(2010) (269) ITT: 711 / 1006 =
71% LOE: moderate
TE
Total 1179 84% (79 - 85)
ITT: 817 / 1179 =
69%
C EP
AC
ACCEPTED MANUSCRIPT
42
PT
Table 2 : ESWL + Endoscopy Medium term FU 2 5 y
RI
(year) (ref)
Sauerbruch Retrospective 24 patients: ESWL, EPS Pain relief
SC
Pain relief more
(1992)(250) observational 83% Pancreating assessment
men, 63% OH often in patients
stenting: 8% pain frequency/m with complete
U
Age: 46 y Technical success:
67% Complete pain relief: stone clearance
Duration of
AN
12/24 (9/10 vs 3/14)
disease: 5 y Complete MPD
clearance: 42% Partial pain relief: 8/24 No statistical
Severe CP: -- Complete or partial analysis
M
(10 / 24)
Pain: 100% pain relief: 83%
FU: 24 m Surgery: 8% LOE : low
Diabetes: --
D
Steatorrhea: --
TE
Costamagna Prospective 35 patients: ESWL (n=35) Pain relief
(1997)(272) observational 89% EPS (n=34) assessment: NA
men, 83% OH
EP
Pancreating
stenting: 51% Complete pain relief:
Age: 46.3 y 23/32 = 72%
Duration of Technical success:
C
disease: 3.3 y 86%

( MPD )
AC
Severe CP: 95%

Complete MPD
Pain: 100%
clearance: 74% LOE : low
FU (n=32): 26.8 m
Diabetes: 37%
Steatorrhea: 11%
ACCEPTED MANUSCRIPT
43
PT
Adamek Retrospective 80 patients: ESWL (n=80) Pain relief No association
(1999)(265) observational 78% Pancreating assessment: NA between clinical
RI
men, 75% OH stenting: NA improvement
Technical success: Complete or partial and technical
Age: -- pain relief: 61/80 =
SC
Duration of 43/80 = 54% success
(complete or partial 76%
disease: -- MPD clearance + No analgesia: 43/80 =
Severe CP: --
U
pancreatic stenting) 54%
Pain: 100% Surgery: 8/80 = 10%
AN
FU: 40 m
Diabetes: 26% LOE : low
Steatorrhea: 24%
M
D
Farnbacher Retrospective 125 patients: ESWL (n=114) Pain relief No association
(2002)(235) observational 81% Pancreatic stenting assessment: NA between relapse
TE
men, 66% OH (n=70) of pain (44/84)
Technical success: Immediate pain relief and
Age: 48 y Complete: 94/101 =
EP
Duration of 85% (106/125)
Complete MPD
93% Continued
disease: 5.9 y consumption of
Severe CP: -- clearance: 64/125 = Sustained pain relief
C
51%
alcohol
Pain: 86% Complete: 40/84 =
Complete vs partial
AC
(Type A: 72%) 48%

MPD clearance
FU (n=84): 29 m Surgery: 15/114 = 13%
Diabetes: --
Steatorrhea: --
LOE: low
ACCEPTED MANUSCRIPT
44
PT
Kozarek Retrospective 40 patients: ESWL (n=40) Pain relief assessment
(2002)(273) observational 53% EPS (n=40) VAS
RI
men, 58% OH
yearly
Age: 53 y hospitalizations
SC
Duration of narcotic medication
disease: 5.9 y monthly
Severe CP: --
U
Complete or partial
Pain: 100%
pain relief: 32/40 =
AN
FU: 2.4 y LOE: low
80%
Diabetes: -- Surgery: 20%
Steatorrhea: 10%
M
Inui Retrospective 555 patients: ESWL alone: n=318 Pain relief
(2005)(263) multicenter: 84% ESWL + Endoscopy: assessment: NA
D
11 centers men, 77% OH
n=237
Complete or partial
TE
Age: 52.5 y Technical success: --
Complete MPD pain relief: 382/504 =
Duration of 76%
disease: -- clearance: 403/555
Surgery: 22/504 = 4%
EP
Severe CP: -- = 73%
Pain: 85% LOE: low
C
FU (n=504): 44.3 m
Diabetes: --
AC
Steatorrhea: --
ACCEPTED MANUSCRIPT
45
PT
Cahen Prospective 39 patients 19 endoscopy / 20 Pain relief assessment Low technical
RI
(2007)(232) randomized 19 ET surgery Izbicki pain score at 6 success rate (53%)
controlled 58% men, 16 ESWL (84%) w, 3, 6, 12, 18, 24 m Low duration of
SC
trial 37% OH EPS pancreatic stenting
Pancreatic stenting: Complete pain relief: (6.2 m)
Age: 52 y 3/19 = 16%
16/19 = 84% ESWL and ET
U
Duration of Partial pain relief: 3/19
Median duration of performed in
disease: 16 m
AN
stenting: 6.2 m = 16% different hospitals
Complete MPD
Pain: 100% pain relief: 32%
clearance: 16/18 = LOE: high
M
(Type A: 37%)
89%
FU: 2 y Technical success: Surgery: 4/19 = 21%
D
Diabetes: 21% 53%
Steatorrhea: 68%
TE
Dumonceau Prospective 29 patients ESWL: n=29 Pain relief Factor
(2007)(261) randomized 72% men, Pancreatic stenting: assessment: independently
EP
controlled 69% OH 13/29 = 45% - VAS (intensity) associated with
trial Age: 49 y Technical success: - number of pain absence of pain
Duration of NA episodes/y relapse (whole
C
disease: -- series)
Complete pain relief
AC
- Location of obstructive
Severe CP: 100% At 2 y: 55%: 16/29 calcification in the head
Pain: 100% At 4.2 y: 55%: 16/29
(Type A: 66%) of pancreas (p=0.013)
Need for ERCP: 18/29 = Treatment costs per
FU: 4.2 y
62%
Diabetes: 14% patient 3 times
ACCEPTED MANUSCRIPT
46
PT
Steatorrhea: -- Need for ESWL: 7/29 = higher in the group
24% ESWL + endoscopy
RI
Need for surgery: 3/29 compared to ESWL
= 10% alone
SC
LOE: high
U
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
47
PT
Hirota Retrospective 34 patients EPS Pain relief
(2011)(274) 74% ESWL (n=21) assessment: NA
RI
men, 50% OH Pancreatic stenting
(n=34) Incidence rate of pain
Age: 54.8 y (AP)
SC
Duration of Duration of
0.21 (n=34)
disease: -- pancreatic stenting
0.11 (n=19)
Severe CP: 100% 3.2 m (n=19)
U
0.37 (n=15)
Pain: 100% 27.0 m (n=15) LOE: low
AN
FU: 3.4 y Surgery: 6/34 = 18%
Diabetes: --
Steatorrhea: --
M
Seven Retrospective 120 patients EPS (n=120) Pain relief Factors predicting
(2012)(256) cross- 43% ESWL (n=120) assessment improvement in
D
men, 54% OH
sectional Pancreatic stenting VAS (1 10) narcotic pain
narcotic
TE
study Age: 52 y (114/120 = 95%) medication use
Duration of Technical success: medication
NA Smokers who quit
disease (n=215): 63
Complete pain relief:
EP
smoking after ESWL
m (95% vs 67%, p=0.014)
60/12 = 50%
Severe CP: --
Partial pain relief:
Pain: 100%
C
42/120 = 35%
FU: 4.3 y Complete or partial
AC

Steatorrhea: 53% narcotic medication:
69/91 = 76%
Stop narcotic
medication: 58%
ACCEPTED MANUSCRIPT
48
PT
FU 4 y (n=55) (mean
FU: 7.5 y) LOE: moderate
RI
Need for ESWL:
16/55 = 29%
SC
Need for ERCP:
46/55 = 84%
Need for surgery:
U
9/55 = 16%
AN
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
49
PT
Suzuki Retrospective 916 patients ESWL (n=457) Pain relief
(2013)(264) multicenter: 86% Endoscopy alone assessment: NA
RI
34 centers men, 74% OH (n=83)
ESWL alone (n=202) Early complete or
Age: -- partial pain relief
SC
Duration of Surgery (n=135)
After ESWL: 91%
disease: -- Complete MPD
After endoscopy:
Severe CP: -- clearance: 74%
U
96%
Pain: -- After surgery: 99%
AN
FU: 3.5 y
Diabetes: -- Recurrent pain (most
frequently within 3 y)
Steatorrhea: --
M
After ESWL: 18%
After endoscopy: LOE: low
D
8%
After surgery: 5%
TE Need for surgery after

ESWL/endoscopy:
EP
10/540 = 1.9%
Tandam Retrospective 636 patients EPS (n=636) Pain relief assessment
364 FU 2 5 y
C
(2013)(275) analysis of a ESWL (n=636) - VAS score (0 10)

prospective 272 FU > 5 y Pancreatic stenting: - number of
AC
65%
database men, 0% OH
347/636 = 55% analgesics
Complete MPD - hospitalizations for
Age: -- clearance: 78% pain
Duration of Technical success:
disease: -- 100% (complete or Complete pain relief:
250/364 = 69%
ACCEPTED MANUSCRIPT
50
PT
Severe CP: -- partial MPD clearance) Partial pain relief:
Pain: 100% 93/364 = 26%
RI
FU: 2 - 5 y Complete or partial LOE: moderate
Surgery: 56/636 = 9%
SC
Steatorrhea: 8%
U
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
51
PT
Ohyama Consecutive 128 patients EPS Pain relief assessment Pain relapse
(2015)(266) case series 77% men, ESWL 4-grade scale occurred at an
RI
66% OH Pancreatic stenting: early date in
14/128 = 11% Immediate pain relief: patients with
Age: 51.4 y 115/128 = 90%
SC
Duration of Duration of stenting: incomplete duct
1y Pain relief in complete clearance (39 m
disease: -- MPD clearance: 61/66 =
Severe CP: -- Complete MPD vs 84 m)
U
clearance: 66/128 =
92%
Pain: 100% Pain relief in incomplete
AN
FU: 3.5 y 52%
ductal clearance: 54/62
Diabetes: 22% = 87%
LOE: low
Steatorrhea: -- Surgery: 1/128 = 0.8%
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
52
PT
Table 2S= ESWL + Endoscopy Medium term FU 2 - 5 y Studies 50 patients
Author Design Number of Complete or partial FU Comments (LOE)
RI
(year) (ref) patients pain relief (months)
Adamek Retrospective 80 76% (61 / 80) 40 --
SC
(1999)(265) Complete 54% (43 /
80) LOE: low
U
Farnbacher Retrospective 125 Complete: 48% (40 29 --
(2002)(235) / 84)
AN
ITT: 40 / 125 = 32% LOE: low
Inui Retrospective 555 76% (382 / 504) 44 LOE: low
M
(2005)(263) ITT: 382 / 555 =
69%
D
Seven (2012) Retrospective 120 85% (102 / 120) 52 Factors predicting
(256) Complete: 50% (60 improvement in narcotic
TE
/ 120) pain medication use
Smokers who quit smoking

EP
LOE: moderate
Suzuki Retrospective 916 After ESWL: 91% 42 LOE: low
C
(2013)(264) After Endoscopy:

AC
96%
Tandan Retrospective 636 94% (343 / 364) 24 60 LOE: moderate
(2013)(275) N = 364; Complete: 69%
FU: 2 5 y (250 / 364)
Ohyama Prospective 128 Immediate pain 42 Pain relapse occurred at an
ACCEPTED MANUSCRIPT
53
PT
(2015)(266) relief: 90% (115 / early date in patients with
128) incomplete duct clearance
RI
LOE: low
Total 2288 Complete: 48 69%
SC
Complete or
partial: 76 94%
U
AN
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
54
PT
Table 3 : ESWL + Endoscopy Long term FU > 5 y
RI
(year) (ref)
Delhaye Retrospective 56 patients: EPS: n=56 Pain relief
SC
Long-term
(2004)(255) 82% men, ESWL: n=56 assessment
68% OH clinical success
Pancreating number of associated with:
U
Age: 44 y stenting: 48% hospitalizations for
Duration of Technical success: pain during FU shorter duration of
AN
disease: 5 y 86% disease before ET
(complete or partial MPD Complete clinical absence of ongoing
Severe CP: 100% clearance + MPD ) success
M
Pain: 100% smoking
ET completed: 61% (no hospitalization):
(Type A: 55%) shorter duration of
Mean treatment 17/56 = 30%
ET
D
FU: 14.4 y duration: 28.7 m lower number of
Partial clinical success
Diabetes: 29%
TE
ET ongoing: 18% ERCP procedures
(1 5 hospitalisation):
Steatorrhea: 29% 20/56 = 36%
LOE : low
EP
Complete or partial
clinical success: 66%
Surgery: 12/56 = 21%
C
Tadenuma Retrospective 117 patients: ESWL (n=117) Pain relief Prognostic

AC
(2005)(234) 73% men, Endoscopy (n=65) assessment factors for pain

68% OH Complete MPD 4-grade scale: none, relapse
clearance: 65/117 = mild, moderate, severe
Age: 48 y Incomplete MPD
56% Pain relief (none or
Duration of stones removal
mild): 49/70 = 70%
disease: -- after initial ET; HR
At 3 y after ET:
ACCEPTED MANUSCRIPT
55
PT
Severe CP: -- 57/70 = 81% 3.7, p=0.0067
Pain: 100% At 5 y after ET: MPD stricture; HR 3.4,
RI
p=0.018
FU (n=70): 77.5 m 35/42 = 83%
Diabetes: 36% At 10 y after ET:
LOE : low
SC
(25/70) 13/13 = 100%
Steatorrhea: --
Surgery: 1/70 = 1.4%
U
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
56
PT
Cahen Prospective 39 patients 19 ET / 20 surgery Pain relief Only 2/9 patients
RI
(2011)(276) randomized 19 ET At 7.1 y 31 assessment operated were
controlled 58% remaining patients Izbicki pain score completely free
SC
trial men, 37% OH (7 , 1 lost) of pain after
16 ET / 15 surgery Complete pain relief: surgery (22%)
Age: 52 y 4/16 = 25%
ESWL (16/19)
U
Duration of This suggests
Pancreating stenting Partial pain relief: 2/16 that pain in these
disease: 16 m
AN
(16/19) = 13% 7/16 patients
Median duration of (44%) was not
Pain: 100% pain relief: 6/16 = 38%
stenting: 9.2 m
M
(Type A: 37%) related to MPD
Surgery: 9/19 = 47% obstruction
FU (n=16): 7.1 y
D
Diabetes: 21%
Steatorrhea: 68%
Tandan Retrospective 636 patients: TE EPS (n=636) Pain relief

LOE : high
EP
(2013)(275) analysis of a 272 FU > 5 y ESWL (n=636) assessment
65%
prospective Pancreatic stenting: - VAS score (0 10)
men, 0% OH
C
database 370/636 = 58% - number of

Age: -- Complete MPD analgesics
AC
Duration of clearance: 76% - hospitalization for

disease: -- Technical success: pain
Severe CP: -- 100% (complete or LOE: moderate
Pain: 100% partial MPD clearance)
60%
Diabetes: 24%
ACCEPTED MANUSCRIPT
57
PT
Steatorrhea: 8% Complete or partial
pain relief: 96%
RI
Surgery: 56/636 = 9%
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
58
PT
Table 3S= ESWL + Endoscopy Long term FU > 5 y Studies 50 patients
RI
Delhaye Retrospective 56 66% 173 Long-term clinical success
SC
(2004)(255) Complete: 30% associated with
Shorter duration of disease
U
Absence of ongoing smoking
AN
Shorter duration of ET
Lower number of ERCP
procedures
M
LOE: low
D
Tadenuma Retrospective 70 70% 78 Prognostic factors of pain
TE
(2005)(234) relapse
Incomplete MPD clearance

EP
MPD stricture
C
LOE: moderate
Tandan Retrospective 272 96% > 60 LOE: moderate
AC
(2013)(275)
Total 398 87% (66 96)
ACCEPTED MANUSCRIPT
59
PT
Table 4 : Endoscopy alone (+ ESWL 60% of population) *with FU 24 m
RI
(year) (ref)
Binmoeller* Retrospective 93 patients: EPS Pain relief
SC
Predictive factor
(1995)(236) observational 70% men, Pancreatic stenting: assessment
66% OH associated with
100% (single plastic) severity / long-term
U
Age: 49 y ESWL: 34/93 = 37% frequency of pain response
Duration of
AN
Mean duration of Pain relief at 6 m
disease: 5.6 y Duration of disease
stenting: 15.7 m - complete
7.0 y in non-
Severe CP: -- Mean FU after stent 46/93 = 49%
M
Pain: 100% responders vs 4.1 y
removal: 3.8 y - partial 23/93 = 25%
in responders
FU: 4.9 y Definitive stent
Diabetes: 17% Complete or partial
D
removal: 49/93 = 53% No statistical
Steatorrhea: 9% pain relief: at 4.9 y: analysis
TE
60/93 = 65%
Surgery: 24/93 = 26% LOE : very low
23 patients:
EP
Ponchon Prospective EPS Pain relief Stopped
(1995)(277) standardized 96% men, Pancreatic stenting: assessment analgesic use
100% OH
protocol 100% severity of pain, associated with
C
Age: 47 y
(single plastic) analgesics in MPD by
ESWL: 0%
AC
Duration of complete pain relief:

2 mm (US)
disease: -- Mean duration of 8/23 = 35%
Severe CP: -- stenting: 6 m partial pain relief:
Pain: 100% Mean FU after stent 13/23 = 57%
(Type A: 61%)
removal: 14 m Complete or partial
ACCEPTED MANUSCRIPT
60
PT
FU: 14 m Definitive stent pain relief: 92%
Diabetes: -- removal: 100% Stopped analgesic use: LOE : low
RI
Steatorrhea: -- 17/23 = 74%
Surgery: 3/23 = 13%
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
61
PT
Smits* Retrospective 51 patients EPS (n=31) Pain relief No predictive
RI
(1995)(237) observational 69% Pancreatic stenting assessment factor of clinical
men, 61% OH (n=49) compared with the 6 improvement
SC
(single, plastic) m prior pancreatic after pancreatic
Age: 45 y
ESWL (n=3): 6% stenting stenting
Duration of
U
< 50% of pain
disease: 28.5 m Median duration of < 50% of analgesic use
Severe CP: --
AN
stenting: 6.3 m < 50% of hospitalization
Pain: 100% Median FU after stent Pain relief during
FU: 34 m removal: 28.5 m stenting (n=49)
M
Diabetes: -- Definitive stent
Steatorrhea: -- removal: 31/49 = 63% Complete: 20/49 = 41%
Partial: 20/49 = 41%
D
Complete or partial:
TE
82%
Pain relief after
stent removal (n=31)
EP
Complete: 12/31 =
39% LOE : low
C
Partial: 10/31 = 32%

Complete or partial:
AC
71%
Surgery: 6/51 = 12%

ACCEPTED MANUSCRIPT
62
PT
Dumonceau Retrospective 70 patients EPS (n=70) Pain relief
Factors
(1996)(251) observational 90% men, 80% OH ESWL (n=41): 59% assessment
associated with
RI
Pancreating Intensity of pain
Age: 47 y immediate pain
stenting: 0% graded on a 10-point
Duration of relief
SC
Technical success: scale (VAS)
disease: 4.8 y
75% Immediate pain MPD clearance
Severe CP: -- (complete or partial MPD (p<0.01) (complete or
relief
Pain: 90%
U
clearance) (n=56 patients with pain partial)
(Type A: 31/56=55%)
Complete MPD at admission) Low frequency of
AN
FU: < 2 y clearance: 50% pain attacks (< 2 in the
Complete 41/56 = 2 prior months) (p<0.05)
Diabetes: 37% 73% Factors
M
Steatorrhea: 43% Partial 12/56 = associated with
22% sustained pain
D
Complete or partial: relief during 2 y
95% FU
TE
Pain relief during 2 y
FU Earlier treatment
after onset of CP
EP
(n = 46)
(p<0.005)
Complete 25/46 = Low frequency of
C
54% pain attacks (< 2

Partial 21/46 = during 2 m before ET)
AC
(p<0.05)
46% Absence of MPD
Complete or partial: stricture (p<0.05)
100%
LOE : low
Rsch* Retrospective 1018 patients: EPS: 92% Pain relief No difference in
ACCEPTED MANUSCRIPT
63
PT
(2002)(230) multicenter 71% ESWL: 26% assessment pain relief in
men, 72% OH
(8 centers) Pancreatic stenting: intensity of pain patients with
RI
Age: 50 y 57% (no, weak, different ductal
Duration of Technical success: moderate, strong) pathologies (i.e.
SC
disease: -- 88% strictures vs stones)
Complete MPD complete pain relief: Trend for higher
Severe CP: -- 66%
Pain: 100% clearance: 64% pain relief in
partial pan relief: 19%
U
(Type A: 73%) Completed ET: patients with initial
Complete or partial technical success
AN
599/758 = 79%
FU: 4.9 y Ongoing ET: 159/758 pain relief: 85% (p=0.06)
Diabetes: 23% = 21% Surgery: 238/1018 =
Steatorrhea: 37%
M
23% LOE: moderate
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
64
PT
Dite* Prospective 140 patients: ET: n=64 Pain relief High risk of bias
RI
(2003)(233) randomized 85% EPS: n=64 assessment - pseudo-
men, 88% OH
study Pancreatic stenting: - Melzack score randomization
SC
Age: 41.7 y 33/64 = 52% Complete or partial - unconcealed
72 randomized ESWL: 0% pain relief after ET allocation
U
36 ET / 36 surgery at 5 y FU - lack of baseline
68 non randomized Mean duration of 65% (n=64) (R + characteristics
AN
28 ET / 40 surgery stenting: 16 m NR) - lack of ITT
Technical success:
FU: 5 y 61% (n=36) (R) analysis
62/64 = 97%
Pain: 100%
M
- not powered
Surgery: n=76
Diabetes: 22% - Resection 80%
- lack of optimal
ET
D
- Drainage: 20% (no ESWL, no
TE
repeated ERCP)
EP
LOE: moderate
Vitale* Retrospective 89 patients: Pancreatic stenting Pain relief
(2004)(238) analysis of a 47% (single plastic) assessment
C
men
prospective - pain intensity
Mean duration of
AC
database Age: 48 y score (1 10)

stenting: 5.3 m
Pain: 100% LOE: low
Pain reduction: 62/75
FU (n=75): 43 m = 83%
Reduction in analgesic
medication: 35/75 =
ACCEPTED MANUSCRIPT
65
PT
47%
Surgery: 11/89 = 12%
RI
Eleftheriadis* retrospective 100 patients: EPS, ESWL (n=51) Pain relief 79% of pain
(2005)(239) 75% Pancreatic stenting assessment: NA relapse during
SC
men, 77% OH (single plastic) the first year
Complete or partial after stent
Age: 49 y Median duration of pain relief: 62/100 =
Duration of removal
U
pancreatic stenting: 62% at 27 m after stent
disease: 3 y 97% had relapsed
23 m removal, without
AN
Severe CP: 86% by 24 m
pancreatic stent
Pain: 100% Predictive factor
replacement
FU: 69 m for pancreatic re-
Re-stenting within the
M
FU after stent stenting (n=30)
first year of FU: 30% at
removal: 27 m within 1 y of stent
a median time of 5.5 m
D
Diabetes: 18% removal:
after stent removal
Steatorrhea: 24% presence of PD
Re-stenting at the end
TE
(n=21) (12/21 vs
of FU: 38%
18/79, p=0.002)
Surgery: 4%
EP
LOE: moderate
Costamagna* Prospective 19 patients: Pancreatic stenting: Pain relief
C
(2006)(242) observational 84% 100% assessment: NA

men, 58% OH
AC
(multiple plastic) Complete pain

ESWL: 6/19 = 32% relief: 16/19 = 84%
Age:45 y
Duration of Mean duration of
disease: -- stenting: 7 m
Severe CP: --
Pain: -- LOE: low
ACCEPTED MANUSCRIPT
66
PT
FU: 38 m
Diabetes: --
RI
Steatorrhea: --
Ishihara NA 20 patients: Pancreatic stenting: Pain relief
SC
(2006)(278) 90% n=20 assessment
men, 95% OH EPS 4-grade scale: none,
ESWL: 9/20 = 45% mild, moderate, severe
Age: 52.4 y
U
Pain relief (none, mild)
Duration of Mean duration of stent
AN
after stent removal:
disease: -- patency: 12 m 18/20 = 90%
Severe CP: --
Pain: --
M
FU after stent LOE: low
removal: 10.5 m
D
Diabetes: --
Steatorrhea: --
Farnbacher*
(2006)(240) TE
Retrospective 98 patients:
86%
EPS (n=76)
Pancreatic stenting
Pain relief
assessment
EP
men, 73% OH (single plastic): n=98 VAS (intensity)
Age: 49 y ESWL (n=60)
C
Duration of Mean duration of 53/96

disease: -- Partial pain relief:
AC
pancreatic stenting:
Severe CP: 88% 10 m 22/96
Pain: 89% Complete or partial:
(Type A: 68%)
75/96 = 78% LOE: low
FU after stent Re-stenting: 17/96 =
removal: 3.8 y 18%
ACCEPTED MANUSCRIPT
67
PT
(n=57) Surgery: 22/96 = 23%
Diabetes: --
RI
Steatorrhea: --
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
68
PT
Weber* Prospective 19 patients: EPS: n=19 Pain relief
RI
74% OH n=17 - VAS (intensity 0
SC
(single plastic) 10)
Age: 54 y
ESWL: n=5 (26%) - in pain medication
Duration of
Technical success:
U
disease: 3 y Complete or partial
17/19 = 89%)
Severe CP: 100% pain relief
AN
Pain: 100% at 1 y: 14/19 = 74%
Mean duration of
(Type A: 58%) at 2 y: 11/19 = 58% LOE: low
stenting: 5.6 m
M
FU: 2 y
Diabetes: 26%
D
Steatorrhea: 5%
Retrospective 292 patients Endoscopy: n=150 Relapse-free interval:
TE
Rutter*
(2010)(279) comparative 150 ET: Pancreatic and/or 4.8 7.0 m (for
70% men, bile duct stenting: endoscopy group)
EP
53% OH
n=60
Age: 51.3 y EPS: n=66
Duration of
C
Surgery: n=99
disease: -- Conservative: n=43
AC
Severe CP: -- LOE: very low

Technical success: --
Pain: 28%
(81/292)
FU: 2.8 y
Diabetes: --
ACCEPTED MANUSCRIPT
69
PT
Steatorrhea: --
RI
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
70
PT
Clarke* Retrospective 85 patients: ET in 71 patients Pain relief assessment Factors
RI
(2012)(253) analysis of a 51% EPS: n=43 (61%) - frequency of pain associated with
prospective men, 41% OH ESWL: n=6 (8%) long-term clinical
- discontinuation of
SC
database Age: 41 y Pancreatic stenting: narcotic medications response to ET
Duration of n=53 (75%) Clinical success (n=28 vs n=27)
U
disease: -- Technical success (n=55)
complete or partial: Less constant pain:
Severe CP: -- Complete: 23/55 =
AN
21% vs 52%, p=0.031
Pain: 72% 60/70 = 86% 42% Less daily narcotics:
(Type A: 58%) Partial: 5/55 = 9% 14% vs 56%, p=0.001
Shorter duration
M
Complete or partial
FU (n=63): 4.8 y clinical success: 51% between onset of CP
Diabetes: 8% and start of ET: 4 m vs
D
Steatorrhea: 21% 40 m, p=0.017
TE
No association
with specific
baseline
EP
morphologic
characteristics
C
LOE: low
AC
Weber* Prospective 19 patients: Pancreatic stenting: Pain relief assessment

(2013)(280) observational 63% n=17 - VAS (intensity 0
case series men, 74% OH (single plastic) 10)
ESWL: n=5 (26%) - in pain medication
Age: 54 y
Technical success:
Duration of Complete or partial
ACCEPTED MANUSCRIPT
71
PT
disease: 3 y 17/19 = 89% pain relief
Severe CP: 100% at 5 y: 8/19 = 42%
Mean duration of
RI
Pain: 100%
(Type A: 58%) stenting: 5.6 m Surgery: 3/19 = 16% LOE: very low
SC
FU: up to 5 y
Diabetes: 26%
Steatorrhea: 5%
U
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
72
PT
He* prospective 360 patients: ESWL: 0% Pain relief Mild CP in 36% of
RI
(2014)(254) 89 stage I M-ANNHEIM EPS assessment patients (i.e. no
classification Stone extraction: Izbicki pain score abnormality of the
SC
72%
men, 38% OH
36/89 = 40% before ET, at 24 m MPD) but 87% of
Pancreatic stenting: Complete pain relief: pancreatic stenting
Age: --
U
76/89 = 87% (single 54/83 = 65% to treat MPD
Duration of plastic) Partial pain relief: stricture!
AN
disease: -- Technical success: 18/83 = 22% Better clinical
Severe CP: 36/89 = NA Complete or partial results if early
40%
M
pain relief: 87% treatment (before
Mean duration of
Mild CP: 32/89 = pancreatic
36%
pancreatic stenting: 11 Surgery: 4/89 = 4% endocrine/exocrine
D
m
Pain: -- insufficiency)?
FU (n=83): 24 m
Diabetes: 0%
Steatorrhea: 0% TE LOE: low
C EP
AC
ACCEPTED MANUSCRIPT
73
PT
Table 4S= Endoscopy ESWL (
50%) Studies 50 patients and FU 24 m
RI
Binmoeller Retrospective 93 65% (60 / 93) 59 Predictive factor of long-
SC
(1995)(236) term response
U
AN
LOE: very low
Smits Retrospective 51 43% (22 / 51) 34 LOE: low
(1995)(237)
M
Rsch Retrospective 1018 85% (865 / 1018) 59 LOE: moderate
(2002)(230)
D
Dite Prospective 64 66% (42 / 64) 60 LOE: moderate
TE
(2003)(233) partially
randomized
Vitale Retrospective 89 70% (62 / 89) 43 LOE: low
EP
(2004)(238)
Eleftheriadis Retrospective 100 62% (62 /100) 69 LOE: moderate
(2005)(239)
C
Farnbacher Retrospective 98 77% (75 / 98) 46 LOE: low

AC
(2006)(240)
Rutter Retrospective 150 ND 34 LOE: very low
(2010)(279)
Clarke Retrospective 55 51% (28 / 55) 58 Predictive factor of long-
(2012)(253) term response
ACCEPTED MANUSCRIPT
74
PT
Less constant pain
Less daily narcotics
RI
SC
LOE: low
He Prospective 89 81% (72 / 89) 24 LOE: low
(2014)(254)
U
Total 1657 78% (43 85)
AN
(1288 / 1657)
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
75
PT
Table 5 : SEMS in MPD for CP
RI
SC
(year) (ref)
Eisendrath Retrospective 38 patients: UC- SEMS: n=20 Pain relief
(1999)(243) observational 89% OH PC (n=9) / FC (n=9) - assessment: NA
U
SEMS
Age: Immediate pain relief
AN
42 y (n=20)
Technical success: 20/20 = 100%
38 y (n=18)
20/20 = 100% 16/16 = 100%
M
Duration of 16/18 = 89%
(migration) Sustained pain relief
disease: --
at 2 y
Severe CP: --
D
3/20 = 15%
Pain: -- LOE : low
TE
4/16 = 25%
FU (n=20): 70 m
Diabetes: -- Surgery: 2/38 = 5%
Steatorrhea: --
EP
Park Prospective 13 patients: FC SEMS (Niti D-type) Pain relief
(2008)(244) pilot study 69% men, assessment: NA
Duration of stenting: 2
C
62% OH
m No pain relapse during
AC
Age: 51 y Technical success: the 5 m FU after stent

Duration of 100% removal
disease: --
Severe CP: --
Pain: 100%
FU after stent LOE : low
ACCEPTED MANUSCRIPT
76
PT
removal: 5 m
Diabetes: --
RI
Steatorrhea: --
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
77
PT
Sauer Prospective 6 patients FC- SEMS (Viabil) Pain relief assessment
RI
(2008)(245) pilot study 67% men, EPS: 6/6, ESWL: 4/6 - VAS before, 4 w after
67% OH stent placement, 4 w
SC
Technical success: after stent removal
Age: 55 y 100%
Duration of disease: Stent removal: 5/6 Complete pain relief: 2/5
U
-- (1 pancreatic cancer) Recurrent symptomatic
Severe CP: -- Duration of stenting: 3
AN
MPD stricture: 3/5
Pain: 100% m Pain score improved:
FU: -- LOE : low
4/6 (67%)
M
Diabetes: --
Steatorrhea: --
prospective 32 patients:
D
Moon FC SEMS (Niti-S, Pain relief
(2010)(246) 84% men, bumpy type), EPS assessment: NA
TE
59% OH ESWL: 19/32 = 59%
Recurrent symptomatic
Age: 48 y Technical success: stricture: 3/32 = 9%
EP
Duration of disease: 100% Complete pain relief:
-- Duration of stenting: 3 27/32 = 84%
Severe CP: -- Surgery: 1/32 = 3%
C
m
Pain: --
AC
FU after stent LOE: low

removal: 5 m
Diabetes: --
Steatorrhea: --
Giacino Case series 10 patients: EPS Pain relief
80% men,
ACCEPTED MANUSCRIPT
78
PT
(2012)(247) 60% OH FC SEMS assessment: NA
(1 biliary WST, 9 biliary
Age: 55.7 y Complete pain relief:
RI
WFX)
Duration of disease: 6/10 = 60%
-- Technical success: Partial pain relief: 3/10
SC
Severe CP: 100% 100% = 30%
Pain: 100% Duration of stenting: Complete or partial
FU after stent 5.7 m
U
pain relief: 90% LOE: low
removal: 20 m Surgery: 0%
AN
Diabetes: --
Steatorrhea: --
M
Table 6 : ESWL alone
D
TE
(year) (ref)
Ohara Prospective 32 patients: ESWL alone (n=32) Pain relief
Severe MPD
EP
88% OH stricture: 10/32 =
0% frequency 31%
Age: 57 y Technical success:
Complete pain relief: Steatorrhea: 2/32
C
Duration of 79% (15/19)

22/28 = 79% = 6%
( MPD )
AC
disease: -- Partial pain relief: 2/28 No statistical

Complete MPD
Severe CP: -- = 7% analysis
clearance: 24/32 =
Pain: 88% Complete or partial
75%
FU: 44 m pain relief: 86%
Diabetes: -- Need for ERCP: 3/32 = LOE : low
Steatorrhea: 6%
ACCEPTED MANUSCRIPT
79
PT
9%
Need for surgery: 1/32
RI
= 3%
Inui Retrospective 555 patients: ESWL alone: n=318 No separate
SC
(2005)(263) multicenter: 84% men, Spontaneous stone outcome for patients
11 centers 77% OH treated by ESWL
clearance: 222/318 =
Age: 52.5 y 70% alone
U
Duration of
AN
disease: --
Severe CP: --
Pain: 85% LOE : low
M
FU (n=504): 44.3 m
Diabetes: --
D
Steatorrhea: --
TE
C EP
AC
ACCEPTED MANUSCRIPT
80
PT
Dumonceau Prospective 26 patients ESWL alone: n=26 Pain relief Factor
RI
(2007)(261) randomized 85% assessment independently
trial men, 73% OH Technical success: NA - VAS (intensity) associated with
SC
Age: 51.8 y - number of pain absence of pain
Duration of episodes/y relapse (whole series)
U
- Location of obstructive
disease: -- Complete pain relief calcification in the head
Severe CP: 100%
AN
- at 2 y: 16/26 = 62% of pancreas (p=0.013)
Pain: 100% - during whole FU at
(Type A: 62%)
4.3 y: 15/26 = 58%
M
FU: 4.3 y Treatment costs per
Need for ERCP: 8/26 =
Diabetes: 23% patient 3 times
D
31%
Steatorrhea: -- lower in the group
Need for ESWL: 7/26 = ESWL alone
TE
27% compared to ESWL
Need for surgery: 1/26 + endoscopy
= 4%
EP
LOE : high
Suzuki Retrospective 202 patients ESWL alone No separate
C
(2013)(264) multicenter: Complete MPD outcome for patients

AC
34 centers clearance: 49% treated by ESWL LOE: very low

alone
ACCEPTED MANUSCRIPT
81
List of Abbreviations in the Tables
PT
ESWL : extracorporeal shockwave lithotripsy
FU : follow-up
RI
y : year
ref : reference
CP : chronic pancreatitis
SC
OH : alcohol etiology of chronic pancreatitis
EPS : endoscopic pancreatic sphincterotomy
MPD : main pancreatic duct
: diameter
U
AN
VAS : visual analogue scale
LOE : level of evidence
very low: < 100 patients, retrospective, no assessment of pain relief, no statistical analysis
M
Low: < 100 patients, retrospective or prospective, subjective or objective pain relief assessment
Moderate: 100 patients, retrospective or prospective, objective pain relief assessment
D
High: RCT, 100 patients, prospective, objective pain relief assessment, identification of
significant predictive factor of pain relief
TE
# : stone(s) fragmentation
NA : not available
m: month
EP
ND: not determined

ITT: Intention To Treat analysis
C
ET: Endoscopical therapy

AP: acute pancreatitis
AC
: dead
US: ultrasonography
R: randomized
NR: non randomized
PD: pancreas divisum
UC-SEMS: uncovered self expandable metal stent
PC-SEMS: partially covered expandable metal stent
ACCEPTED MANUSCRIPT
82
FC-SEMS: fully covered expandable metal stent
PT
RI
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
83
Harry van Goor, Tonya M Palermo & Eva Szigethy
PT
Q9. Are other treatments (neurolytical, psychological, ect.) effective for pain management
in CP?
Neurolytical interventions can be used in selected patients with painful CP who have failed
RI
endoscopic and surgical treatment. Thoracoscopic splanchnic denervation is more effective
regarding long-term pain relief in patients who are not in chronic opioid treatment. Behavioral
interventions should be part of the multidisciplinary approach in CP pain particularly when
SC
patients experience psychological impact of pain and quality of life has decreased. Early
intervention in children may be particularly important.
(Quality assessment: low, recommendation: strong; Agreement: conditional)
U
This chapter comprises two different types of pain treatment in CP, nerve ablation (neurolytic)
AN
and psychological or psychiatric intervention. Consequences of CP in children and psychological
treatments are addressed in a separate paragraph to create awareness for this small but
underexposed group of patients with chronic pain. Overall the evidence of these types of
M
treatments regarding pain relief is low due to lack of good quality trials.
Neurolytic interventions
D
Neurolytical treatments of patients with chronic pancreatitis pain are generally implemented
when other medical treatments have failed and patients are referred to pain specialist teams.
TE
Treatment is only recommended in patients not responding to conventional analgesics and/or

having severe side effects of medication, in patients who have no pathology suitable for surgery
or endoscopy or are not willing to undergo these treatments. Commonly this is done at a late
EP
disease stage when patients have suffered longstanding intractable pain, despite numerous
treatments and are desperately seeking pain relief (last resort). As a result, studies of nerve
ablation interventions are predominantly done in populations of patients with severe chronic
C
pancreatitis pain, are heterogenous, include fairly low quality trials, and often fail to demonstrate
AC
a long term beneficial effect. Finally, as a sham arm has never been used it is not known whether
the effects are a result of the intervention per se or reflects the natural course of the disease.
Neurolytical treatments can be at different levels of the visceral afferent system; celiac plexus
block (percutaneous fluoroscopy or CT guided), surgical, endoscopic ultrasound (EUS) assisted),
splanchnic nerve ablation (surgical, percutaneous). Other treatment (although not neurolytical)
are stimulation of central parts in the brain (spinal cord and transcranial magnetic resonance
(TMS) stimulation).
Several techniques for percutaneous celiac plexus blockade have been described(281) but pain
relief only lasts for several weeks to months and in about half of patients with no long term
ACCEPTED MANUSCRIPT
84
benefits. EUS-guided celiac plexus blockade was effective in alleviating abdominal pain in
51.46% of patients based on a systematic review of 6 studies comprising a total of 221
PT
patients(282). Although endoscopic ultrasonore guided plexus block was superior to
percutaneous CT guided block in 2 RCTs regarding duration of pain relief, long term pain relief
was insufficient or not investigated(283). Furthermore, there is a risk for side effects such as
RI
postural hypotension and diarrhea. After a short-lived period of use, endoscopic ultrasonore
guided celiac plexus block is nowadays rarely applied.
Thoracoscopic splanchnicectomy was first described as minimally invasive therapy for pain in
SC
1994(284) and has been researched by several groups in the world since then; however, to date
no RCT has been done. In a recent review of sixteen studies with 484 patients with thoracoscopic
splanchnicectomy and a minimum follow-up of 12 months, a median of 49% of patients were
U
free of opioids at end of follow-up(283). Similar to pancreatic surgery for chronic pancreatitis,
preoperative opioid use and duration of disease and pain seem to impair long term results
AN
probably due to central sensitization(285). Splanchnicectomy early in the disease course and
before opioids are started could be an attractive alternative to early pancreatic surgery, but this
needs to be further researched in a trial. Even less invasive is percutaneous splanchnic nerve
M
radiofrequency ablation. Only retrospective small series are reported with good effects, however,
for a short period(286). Advantage of this technique is the possibility to repeat the ablation
without much morbidity.
D
There are only a few retrospective studies of spinal cord stimulation and case reports in
transcranial magnetic stimulation (TMS) in chronic pancreatitis(287,288). Pain relief for more
TE
than a year was achieved in 66 percent of patients with severe chronic pancreatitis who had
spinal cord stimulation. Drawback of the procedure is the invasiveness and potential for implant
infection(287). Repetitive TMS holds promise for treating depression in chronic pancreatitis
EP
patients with a possible concurrent pain relieving effect, but this needs to be investigated in more
homogenous groups of patients and with validated techniques.
C
Psychological/psychiatric interventions
AC
Pain in CP is multi-determined and underlying etiology is not well delineated though features of
nociceptive, visceral, neuropathic and central mechanisms have been implicated. In other disease
populations, chronic non-cancer pain is associated with depression-anxiety spectrum
disorders(289291) and substance misuse or abuse(292,293), which if unaddressed, can further
complicate treatment of pain. Post-traumatic stress disorder is also associated with chronic pain
(294,295). Consistent with common psychosocial impact experienced by other patients with
chronic pain, patients with CP also report high rates of depression, substance use, and poor
quality of life(54,296,297). Severe chronic pancreatitis pain is also associated with declines in
cognitive performance (e.g psychomotor performance, memory, and executive functions)(298);
ACCEPTED MANUSCRIPT
85
the co-occurrence of depressive symptoms, sleep disturbance, opioid use, and history of alcohol
abuse also predicted cognitive decline.
PT
There are a paucity of studies examining the effects of psychological interventions for CP
patients. In other chronic pain conditions and gastrointestinal disorders, psychological
interventions have shown to be efficacious in reducing chronic pain and pain impact(299,300).
RI
Behavioral interventions with the most support for chronic pain include cognitive behavioral
therapy (CBT), acceptance therapy, mindfulness approaches, and hypnosis(301304). There is
also growing evidence supporting the neurobiological processes involving the brain-gut axis
SC
which increasingly accepted as mediating the effects of psychological interventions(305).
In one study of 311 CP patients captured during inpatient admissions, a collaborative
interdisciplinary treatment program, which included psychological and psychiatric interventions,
U
was associated with reduced healthcare costs(306). The psychological care included
comprehensive psychosocial evaluations about the pain experience, depression, anxiety, post-
AN
traumatic stress disorder, substance use/misuse, coping styles, past psychiatric treatment, social
support and educational/vocational achievement. Personalized psychological interventions
included behavioral approaches to pain management (relaxation, guided imagery), biofeedback,
M
hypnosis, and various psychotherapy modalities (acceptance-based, CBT, brief dynamic, and
interpersonal). Psychiatric intervention included psychotropic medications targeting depression
and anxiety, optimization of non-opioid pain medications (e.g., gabapentin, SSRI/SNRI,
D
analgesics), screening for and treatment of addiction including buprenorphine/naloxone) and

opioid tapers. The study, however did not have a comparison group and did not include
TE
standardized treatment protocols, thus it is not possible to attribute cost reduction directly to
behavioral interventions.
Chronic opioid management is often necessary for residual pain, which increases the risk of
EP
addiction and misuse(307,308). Identification of risk factors for opioid addiction is critical(309).
In one study, clinical risks for opioid misuse in patients with chronic nonalcoholic pancreatitis
included depression, poor quality of life and alcohol use(297). Behavioral intervention and
C
psychosocial resources are critical to prevent or treat opioid misuse and dependence in patients
AC
with CP(310). A strong empathic doctor-patient relationship is also key. Successful opioid
detoxification strategies have also been demonstrated, though recidivism was high at 6
months(311).
Children with CP pain

Children with CP represent an important subgroup who experiences frequent pancreatitis-related
abdominal pain(312), reduced quality of life and significant problems with fatigue(313). Similar
to the impact of chronic pain in other pediatric chronic conditions, children with chronic CP also
have severe disease burden, high health care utilization and costs(314). Moreover, children also
ACCEPTED MANUSCRIPT
86
experience the functional impact of CP on their ability to attend school. In one study, 70% of
children with CP indicated one or more missed days of school in the past month due to chronic
PT
pancreatitis and one-third of children had missed 3 or more days of school in the most recent
month(315). Additional research is critically needed to understand the epidemiology of chronic
pancreatitis pain in children, risk factors for chronic pain and poor quality of life, and treatment
RI
approaches that may improve pain and quality of life for children. Longitudinal research will be
particularly informative for understanding trajectories of pain into adulthood. Because CP pain
and its impact have only recently been recognized in the pediatric population, there are no
SC
studies of neurolytical or psychological treatments conducted to date. Psychological treatments
for other forms of pediatric chronic pain, including abdominal pain, are well studied and have
promising effects. Treatments have included predominantly cognitive-behavioral interventions
U
such as pain education, relaxation training, pain-specific cognitive therapy, and behavioral
activation. Social learning theories have also guided treatment in children where intervention
AN
strategies focus on modifying parent behavior that may inadvertently reinforce maladaptive
coping (such as teaching parents to reward activity participation like attending school). In the
most recent systematic review of the efficacy of RCTs of psychological therapies for a range of
M
pediatric chronic pain conditions including abdominal pain(316), moderate effects on pain and
small effects on reducing disability were found at post-treatment. Unfortunately, even when
effective psychological treatments are developed major barriers exist for families to access
D
specialized pediatric pain services due to the geographical distance that separates most families
from pediatric pain specialists. Very limited clinical resources are available to treat pediatric
TE
chronic pain and this shortage of treatment centers(317) has been identified as a major barrier
contributing to an unmet clinical need. Availability of information and communication
technology has expanded opportunities for reaching families remotely. An emerging evidence
EP
base now exists for internet-delivered psychological interventions for chronic pain in both adult
and pediatric populations(318320), with patients showing improvements in pain and disability.
A major priority in treatment of chronic pancreatitis pain is to develop and evaluate low-cost
C
psychological treatments to reduce pain and improve quality of life both for children and adults.
AC
ACCEPTED MANUSCRIPT
87
Gralp O Ceyhan, Harry van Goor and Stefan A W Bouwense
PT
Q10. What is the optimal surgical approach to relief pain in chronic pancreatitis
Depending on the morphological changes of the pancreas and pain processing status a
(partially) resection, decompression of the pancreatic duct or combined intervention can be
RI
performed to reduce pain. Long-term effects are variable, however success rates up to 80% have
been reported. The emerging role of total pancreatectomy as initial surgical treatment looks
promising but needs further investigation (Quality assessment: moderate; Recommendation:
SC
strong; Agreement: conditional)
U
Four groups of pathophysiological mechanisms have been suggested to cause pain in chronic
pancreatitis: 1) inflammation of the pancreas; 2) increased intrapancreatic pressure within the
AN
parenchyma and/or pancreatic duct, causing tissue ischemia; 3) (late) pancreatic and
extrapancreatic complications (e.g. pseudocysts, portal thrombosis, bile duct/duodenal strictures
and peptic ulcers) and 4) alterations indicative of nerve damage, e.g. increased number and
diameter of pancreatic nerves, and inflammation of perineural sheathes have been described in
M
chronic pancreatitis together with changes in the central nervous system (peripheral and central
sensitization)(42,103,199,321,322).
D
How these different pathophysiological mechanisms exactly cause pain in chronic pancreatitis
and which correct time point for surgerical procedures is most appropriate are still under debate.
TE
In many centres invasive treatment is recommended in patients where pain cannot be controlled
without the use of opioids and endoscopic interventions have failed or are not indicated.
Although long-term results of surgery are promising, most of studies to date are observational or
only compare different invasive procedures. Question if surgery, when performed early, is better
EP
than opioid treatment or early endoscopy cannot be answered till now. The different studies have
also compared surgical techniques or surgery vs. Endoscopy, and as no studies have used a sham
control the natural history of disease and placebo effects have not been taken into consideration
C
and data must be interpreted causiously.

Surgical options for pain are classified into three categories: a) decompression (focusing on
AC
ductal hypertension), b) resection (focusing on inflammatory masses and stones in the pancreatic
head) and c) mixed techniques.
In the 1950s, Puestow and Gillesby developed a technique combining a longitudinal opening of
the pancreatic duct and an anastomosis to the small intestine with a pancreatic left resection
which is still applied nowadays for pancreatic stones and pseudocysts. Another technique by
Partington and Rochelle is a modificaton of this procedure with an extended opening of the
pancreatic duct and a preservation of the pancreatic tail. Surgical procedures for painful CP aim
at the resection of the pancreatic inflammatory mass, such as (1) the standard Kausch-Whipple
procedure with resection of the pancreatic head, gallbladder, duodenum, and gastric antrum, (2)
ACCEPTED MANUSCRIPT
88
the Traverso-Longmire procedure, a pylorus-preserving pancreaticoduodenectomy, (3) the Beger

procedure, a resection of the pancreatic head that preserves the duodenum and intrapancreatic
PT
bile duct by subtotally excising the head and uncinate process, (4) the Frey procedure, a variation
of the Beger procedure that combines longitudinal pancreaticojejunostomy with a local
pancreatic head excision without transection of the pancreas above the portal vein, (5) the
Berne/Farkas technique, a partial resection of the pancreatic head without a lateral
RI
pancreaticojejunostomy that avoids the transection of the pancreas above the portal vein and
combines the advantages of the Beger and Frey operations. Depending on pathology and
SC
location, other organ-preserving procedures include (6) the V-shape excision of the ventral
pancreas, (7) the middle segmental pancreatic resection, (8) the pancreatic left resection or (9)
total pancreatectomy.
U
Data on early surgical intervention might be associated with improved postoperative pain relief
compared to delayed surgery after repeated endoscopic interventions(323). A randomized trial on
AN
early surgery compared to the normal step-up approach (medication, followed by endoscopy
and finally surgery when needed) has nearly finished and will provide us with data on the timing
of surgery in chronic pancreatitis(324). In several randomized controlled trials, tailored organ-
M
sparing procedures, such as the Beger or Frey procedures, have been found to be superior to the
classic Whipple or the pylorus-preserving Whipple procedure in regard to pain relief (75%) and
morbidity (20%)(325,326). In addition, independent randomized trials revealed that the Frey
D
procedure provides a better quality of life, while the pylorus-preserving

pancreaticoduodenectomy and the Frey procedure were found effective in long term pain relief
TE
(82-100%) and morbidity (17%)(327,328). Long-term follow-up showed comparable pain

control and pancreatic function between both procedures, while survival rates were superior after
the Frey procedure. In a prospective, randomized trial on different techniques of duodenum-
EP
preserving pancreatic head resection, the Beger and the Frey procedures were found to be
equally safe and effective in pain relief(329). About ten years later, a long-term follow-up
showed no difference in pain control within the two groups(330). In addition, a controlled,
C
prospective, randomized study on the evaluation of the Beger and Berne procedures for CP
showed the Berne technique to provide significantly shorter operation times and hospital stays,
AC
while the quality of life was found to be similar(331). However, ten-year follow-up did not show
any differences in patient-relevant outcome parameters between the Beger and Berne
procedures(332). In a randomized trial on pylorus-preserving and duodenum-preserving
pancreatic head resections, both types of resections were found to be equally effective in pain
relief and quality of life without differences in exocrine or endocrine pancreatic function(326).
An indication for total pancreatectomy (with/without islet autotransplantation) is to palliate pain,
especially after diabetes mellitus has developed. If performed early the clinical results of total
pancreatectomy on pain relief look promising. Further trials are needed to provide high grade
evidence on timing and efficacy of this procedure(333,334).
ACCEPTED MANUSCRIPT
89
Important phenomenon in chronic pain disorders like chronic pancreatitis is the change in central
PT
nervous system pain processing like peripheral and central sensitization. When sensitization is
present painful stimuli become more painful and endoscopic and/or surgical therapy has a higher
risk of failure. Factors that are relevant in developing sensitization are duration of the disease,
age, pain history and previous invasive treatment(103).
RI
In summary, surgery has to be tailored to the needs of patients and should be problem-oriented
SC
and preferably organ-sparing, and performed after thorough evaluation in an interdisciplinary
setting in a high-volume center with expertise in pancreatic surgery. The success of surgery (or
other invasive treatments) depends on the cause of pain and the nervous sytem status of
processes painful stimuli (e.g. peripheral and central sensitization)(103,285,335). In this context,
U
the pain processing status needs to be taken into account decising for surgery and the indication
of surgery should be considered early once symptoms are unambiguous and opioids are needed.
AN
With regards to the surgical method, the duodenum-preserving pancreatic head resections
(including Beger, Frey, and Berne procedures) have been shown to be superior to the classic
Whipple procedure, while Frey, Beger and Berne procedures have similar results when being
M
compared to each other. Thus, the choice of procedure should be determined by other factors,
such as the presence of secondary complications of pancreatitis, intra-operative findings and
individual experience of the surgeon(336).
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
90
Ihsan Ekin Demir and Gralp O Ceyhan
PT
Q11. When is the optimal time for surgery in painful CP?
Current evidence on the timing of surgery for painful CP suggests a beneficial role for early
surgery, i.e. 1) within the first 2 to 3 years after diagnosis or symptom onset, 2) for patients who
RI
had equal to or fewer than 5 endoscopic procedures, and 3) for patients who have not yet
required opioid analgesics for medical pain treatment (Quality assessment: low;
Recommendation: weak; Agreement: strong).
SC
Pain, when refractory to medical treatment, represents one of the leading indications for surgery
on patients with chronic pancreatitis (CP). Depending on the morphology of the pancreatic duct
U
and the extent of inflammatory alterations in the pancreatic head, pancreatic drainage or
resection procedures can be performed. For either type of surgery, high rates of postoperative
AN
pain relief of around 60-90% has been reported in numerous studies(337339), including
randomized controlled trials (RCTs)(232). Despite this effectiveness of surgery in the treatment
of CP-associated pain, the time when a patient is referred to surgery, and the time point when a
M
medical treatment is assumed to have failed, varies extensively between centers. Due its
technical complexity and its perceived potential mortality/morbidity, pancreatic surgery does still
not find frequent use for patients with a long-history of CP-associated pain. However, in the
D
largest series, the overall mortality and morbidity after surgery for CP has been reported to lie
only around 1% and 20-30%, respectively(338). Despite these acceptable figures, CP patients
TE
with severe pain requiring opioid analgesics are rarely referred to surgery in the first years after
diagnosis. Rather, endoscopic measures are applied, yet evidence for the effectiveness of
endoscopic interventions in the early phase of CP with regard to short or long-term pain relief, is,
EP
when compared to surgery, weaker(340), for detailed information see the endoscopy section.
Currently, although there are no prospective controlled studies that specifically addressed the
timing of surgery for painful CP, increasing amount of evidence suggests that surgery should be
C
considered early for better pain outcomes. In a systematic review that analyzed the role of
AC
timing, Yang et al. found that the definition of early versus late was variable between
eligible studies(323). Still, the concordant finding from 11 studies was that early surgery was
associated with a greater probability to attain postoperative pain relief (RR=1.67, 95% CI: 1.09-
2.56, p=0.02)(323). Moreover, in the meta-analysis of two studies, early surgery was associated
with an increased likelihood of complete postoperative pain relief. In these two studies, early
surgery was performed within the first 21 months after symptom onset (Cahen et al., 2007), or
within 5 years of clinical disease(233). In a retrospective series, preoperative duration of CP for
greater than 3 years tended to results in higher postoperative pain persistence rates (43% vs.
37%)(337). Clarke et al. reported somewhat better rates of pain relief after surgery for CP within
ACCEPTED MANUSCRIPT
91
54 months versus for 87 months after diagnosis(253). In a recent institutional retrospective study
from the USA including 66 patients, Yang et al. calculated the optimal cutoff point for
PT
preoperative CP duration to reach best possible pain relief after surgery, and found 26.5 months
or less after diagnosis to yield the best outcome(341). Furthermore, they identified shorter
duration of CP before surgery as a predictor of pain-free status and reduced postoperative opioid
RI
use(341).
Beyond the duration of CP, preoperative opioid use, or the frequency of endoscopic interventions
also seems to influence the postoperative pain relief rates. Alexakis et al. analyzed the
SC
characteristics of 112 CP patients who underwent surgery, and found longer duration of pain and
CP-associated symptoms among patients who were on opioids prior to surgery(342). During the
first 24 months of follow-up, patients who had been on opioids preoperatively had greater pain
U
scores after surgery than patients who had not previously used opioid analgesics(342). A similar
observation was made by Ahmed Ali et al. who evaluated 266 CP patients in a cohort study from
AN
five academic centers with a 5-year follow-up(257). Here, they found that surgery within three
years of pain onset was independently associated with more pain relief. Moreover, pain relief
was more common among patients who were not taking opioids preoperatively(257).
M
Interestingly, there was also a correlation between the frequency of previous endoscopic
interventions and postoperative pain relief, since five or more endoscopic interventions resulted
in less frequent pain relief among CP patients(257). In another cohort study with 55 patients
D
from the UK, Terrace et al. analyzed the impact of pancreatic drainage surgery (longitudinal
pancreatico-jejunostomy) with Freys procedure (that involves coring of the pancreatic
TE
head)(343). Here, there were comparable reductions rates in analgesia requirement, but patients
who were not on opiods were likely to be pain-free after surgery than patients who had required
opioids(343).
EP
As also underlined by the recent Cochrane Review on the comparison of endoscopy versus
surgery in the management of painful CP(231), the three RCTs on this topic collectively
demonstrate that surgery is superior to endoscopy with regard to pain relief both at middle-term
C
(2-5 years) or long-term (>5 years) follow-up(232,233,344). Furthermore, early surgery was
AC
proposed to provide better pain relief and pancreatic function when compared to a conservative
approach, yet based on the results of a single, old RCT with a small cohort and absent sample
size calculation(231,344).
ACCEPTED MANUSCRIPT
92
Onset of pain in CP
PT
No
Medical treatment Analgesic treatment
performed as outlined in figures 1 and 2
Yes
RI
Previous
endoscopic No
Yes intervention
SC
Failure of three endoscopic attempts? Obstructive stones that can be removed
via ERCP/ESWL
Yes
No Yes
Patient on opioids?
No Pain persistance after ERCP/ESWL
U
Yes
Yes
EARLY Surgery
Pain persistance after Stenting
AN
No (higher long-term pain
Time elapsed since relief rate) Yes
pain onset >3years? Pain relief after a maximum of three stent
Yes changes?
No
M
Consider surgery
(lower long-term pain
relief rate)
D
TE
Figure 4: Timing of surgery in chronic pancreatitis Surgery is increasingly considered to be more effective for
treating pain in CP, if considered early, i.e. within the 2-3 years after diagnosis, and if only a limited number of
endoscopic therapy attempts (max. 3) have been made. Later surgery, i.e. after three years of diagnosis, may not
provide the same degree of effectiveness in pain relief as early surgery.
EP
Collectively, current evidence on the timing of surgery for painful CP suggests a beneficial role
C
for early surgery, i.e. 1) within the first 2 to 3 years after diagnosis or symptom onset, 2) for
AC
patients who had equal to or fewer than 5 endoscopic procedures, and 3) for patients who have
not yet required opioid analgesics for medical pain treatment (Figure 4). These
recommendations still need to evaluated in the context of novel, better designed RCTs
comparing surgery with other measures in the early phase of CP. Encouragingly, the Dutch
Chronic Pancreatitis Registry (CARE) has already collected detailed records on the pain and
other characteristics of 1,218 patients from 33 hospitals and is likely to provide a solid basis for
the role of early surgery in the management of painful CP. Moreover, the ESCAPE trial (Early
surgery versus optimal current step-up practice for chronic pancreatitis), which is currently
recruiting, represents the most current RCT that will yield important results toward answering
ACCEPTED MANUSCRIPT
93
the question on the timing of surgery for CP(324). In this study, the investigators reported that
patients with a dilated pancreatic duct (5 mm) and moderate pain and/or frequent flare-ups are
PT
going to be monitored for randomization criteria (e.g. need for opioid analgesics)(324). Even
though this requirement for opioid analgetics represents a potential confounder that may mask
the potential beneficial effects of surgery for these patients, this study is still likely to allow a
RI
comparison between the duration of the disease and the benefit from surgery versus medical
step-up treatment. Until the advent of its results and further well-designed RCTs, early surgery
should be assumed to be the superior option in the management of painful CP. However, this
SC
recommendation of early surgery, i.e. drainage (e.g. Puestow) or resection (Beger, Frey or
Bchler), does not hold for total pancreatectomy with islet auto-transplantation (TPIAT), since
this procedure is currently recommended for CP patients with severe impairment of quality of
U
life and for those who are already on opioid analgesics(345). Whether also this more invasive
procedure (that has a higher risk of postoperative diabetes) should be considered at an earlier
AN
phase of painful CP is a matter of current and future investigation.
Finally, more work is needed to establish the etiology of pain and if possible tailor the type of
surgery accordingly. Hence, surgery may not be sufficiently beneficial in patients where the pain
M
has a strong neurogenic origin(346). Although no solid evidence from human studies is
available, it is plausible that such neuropathy may increase over time and thus justify the role of
early surgery. In patients with obstruction of the duct system, surgery may play an even more
D
prominent role, and timing can be decisive for the outcome. Hence, studies that explore pain
mechanisms in CP further are still very much needed.
TE
C EP
AC
ACCEPTED MANUSCRIPT
94
Ihsan Ekin Demir, Shuji Isaji
PT
Q 12. How to manage pain "relapse" after surgery or endoscopy for painful CP?
Current evidence suggests that the first step for the management of pain relapse should be
exclusion of obstructing stones or strictured anastomosis via imaging, followed by a limited
RI
number endoscopic interventions, and early consideration of re-surgery to achieve pain control
(Quality assessment: weak; Recommendation: strong; Agreement: weak).
SC
The management of pain in CP includes medical (medication-based), endoscopic, or surgical
arms. Among these, surgery has been traditionally reserved for cases that are refractory to
medical or endoscopic treatment and proposed as last resort within a step-up approach. Recent
U
data, though, indicate that surgery performed at an earlier phase of CP, i.e. within the first three
years of symptom onset, or prior to numerous endoscopic interventions, may yield clearly better
AN
pain relief than late surgery(323,257). After any type of surgery or intervention, though, pain
relapse in CP is not uncommon. Indeed, even after the most radical and effective type of
intervention, i.e. surgery, the long-term (5-year) pain-freeness lies around 50 to 60% in the
largest series(337339). This figure means that half to 40% of all CP patients who underwent
M
surgery for painful CP are eventually going to develop pain relapse. A recent study showed high
readmission rates at 30 and 90 days after surgery for CP (including duodenum reserving
pancreatic head resection or pancreaticoduodenectomy), reaching 33% at 30 days and 40.5% at
D
90 days, mainly due to inadequate pain control(347). In the medical literature, the management
of these cases of pain relapse either after surgery or even endoscopy has not been sufficiently
TE
addressed, and high-quality studies are lacking.

After endoscopy, some studies with potential selection or publication bias have reported that
persistent pain relief after endoscopic treatment (including endoscopic sphincterotomy, dilatation
EP
of the pancreatic duct, and stent placement) reached 57% at the five-year follow-up(280). For
patients with pancreas divisum who underwent endotherapy, the response rate, i.e. complete or
partial relief rate was reported to be 69.4% and to be comparable to that after surgery
C
(74.9%)(348). In a long-term prospective controlled study, Seza et al. performed extracorporeal

shock-wave lithotripsy (ESWL) or endoscopic basket extraction of pancreatic stones, followed
AC
by stenting or not (control) of the main pancreatic duct(349). The recurrence rates were 15% in
the stented vs. 50% in the control group at the five-year follow-up(349). In a randomized
controlled trial comparing ESWL in combination with endoscopy with ESWL alone, Dumonceau
et al. reported 38% pain relapse after ESWL alone and 45% pain relapse after ESWL combined
with endoscopy(261), rendering the benefit from additional endoscopy after ESWL questionable.
In the largest retrospective cohort (n=636) of ESWL reported in the literature, 68.7% of the
patients were pain-free, 25.4% had mild-to-moderate pain, and 5.5% had severe pain at 2 to 5
years of follow-up. In the long-term group (longer than 60 months follow-up), 60.3% had
no pain, 35.7% had mild or moderate episodes of pain, and 4.04%severe pain(275). Overall,
ACCEPTED MANUSCRIPT
95
these results point out that in well-selected cases, endoscopic interventions may result in around
60% complete pain relief rates in the subsequent five years after the intervention.
PT
However, there seems to be no consensus on the management of pain relapse in CP patients who
underwent previous endoscopic interventions. In a retrospective study with 100 CP patients, only
38 (38%) of CP patients who had underwent endoscopic stenting required re-stenting within the
69-month follow-up period, and these patients were ultimately referred to surgery (pancreatico-
RI
jejuonstomy)(239). In their retrospective series with 14 patients, Weber et al. had 6 patients who
did not respond to endoscopic therapy, and 4 of these patients were treated using repeated stent
SC
therapy or analgesic/medical treatment(280). Only 2 of the 6 patients were referred to surgery.
However, the rationale for the choice of three different strategies in these three pairs of patients
was not delineated in the study(280). In a similar study, the investigators reported pain relapse in
5 out of 17 CP patients (stage III according to Cambridge classification) within the first two
U
years after stent removal, and they speculated that repeated stenting may be an option for these
relapse cases(241). In a recent randomized, double blind, placebo-controlled trial, the 87
AN
narcotic-nave CP patients with pain relapse after endoscopic ductal clearance received either
antioxidant-pregabalin combination therapy (n=42) or matching placebo (n=45) for 2months
followed by open-label antioxidants for the next 4months in both groups(192). In the treatment
M
arm, the combined antioxidant-pregabalin therapy resulted in reduced pain scores, higher
frequency of pain resolution, and reduced number of painful days when compared to
placebo(192). The pain reduction was further persistent at 6 months in the treatment group(192).
D
Therefore, after endoscopic interventions, the evidence for recommending a certain type of
therapy for pain relapse is yet quite immature. However, it seems that endoscopy may provide
TE
adequate pain relief in selected cases, and patients with pain relapse may benefit from few
additional sessions of repeat interventions like stenting, or subsequent medical treatment via
antioxidants together with pregabalin. The caveat behind these observations is that all these
EP
studies with pain relapse after endoscopy did not include a study arm of patients who were
referred to surgery after pain relapse. In fact, previous endoscopic stenting was not identified to
be a risk factor for more or recurrent pain after surgery (pancreatico-jejunostomy)(350).
C
Lack of sufficient evidence for concrete recommendations for managing pain relapse in CP also
holds true for the post-surgery pain relapse. In a series with 39 patients who developed pain
AC
relapse after surgery (resection or drainage operation) from a pool of 316 patients, Howard et al.
found that revision of pancreatico-jejunostomy enabled pain relief in 67% of the patients,
whereas partial resections such as duodenum-preserving pancreatic head resection,
pancreaticoduodenectomy, or distal pancreatectomy achieved pain relief in <50% of the
patients(351). In a long-term follow-up series (10-year follow-up), Talamini et al. also identified
pancreatico-jejunostomy to significantly correlate to a smaller annual number of pain
relapses(352). In another case series, Markowitz et al. performed different types of salvage
operations on 13 CP patients who previously had pancreatico-jejunostomy(353). These
operations included distal pancreatectomy, extension of the pancreaticojejunostomy and
ACCEPTED MANUSCRIPT
96
choledochojejunostomy, biliary stenting followed by choledochojejunostomy, and pancreatico-

duodenectomy(353). Ten of the 13 patients experience considerable or even excellent pain relief
PT
(353). Hence, the type of surgery to be chosen for a re-operation on a CP patient with relapse
may vary, depending on the pancreatic morphology. In all cases, it is crucial to first exclude
more simple reasons for therapy failure such as obvious stricture of anastomosis, or obstructing
stones in the pancreatic or bile duct(354), that can possibly be removed by endotherapy
RI
interventions. Furthermore, it should be considered that a salvage operation for pain relapse may
end up in a total pancreatectomy, which, in patients with predictably low postoperative
SC
compliance, would impose a major problem due to the unavoidable postoperative diabetes
mellitus. In patients with pain relapse after pancreatic surgery, surgeons should consider that any
kind of subsequent treatment may be subject to failure due to the intra- and extrapancreatic
neuropathic alterations that may be irreversible(202)(355). In any case, relapse-free intervals
U
were reported to be longer after surgery for CP when compared to endoscopic treatment(279).
AN
In conclusion, pain relapse after surgical or endoscopic treatment of CP is a frequent and
clinically very relevant problem. Current evidence suggests that the first step for the management
of pain relapse should be exclusion of obstructing stones or strictured anastomosis via imaging,
M
followed by a limited number endoscopic interventions, and early consideration of re-surgery to

achieve pain control. This should be supported by an adequate pain therapy (see pharmacological
pain treatment section), figure 5. Studies that address the management of pain relapse after
D
surgery for CP, and that contain endoscopic and surgical intervention arms in a randomized,
controlled setting are eagerly awaited.
TE
Pain relapse in CP after previous

surgery or endoscopy
EP
No
Refractory to
Analgesic treatment as
medical treatment outlined in figure 1 and 2
Yes
C
Obstructive stones or
anastomotic stricture on
AC
imaging
No Yes
Consider ERCP/ESWL stenting

Organ-sparing surgery possible?
Yes
Yes No Yes
Pain persistance after ductal clearance
Salvage surgery Last resort:

total pancreatectomy
Revision of pancreatico-
jejunostomy (consider the expected
Duodenum-preserving postoperative compliance for
pancreatic head resection diabetes treatment! )
ACCEPTED MANUSCRIPT
97
Figure 5: Management of pain relapse in chronic pancreatitis after surgery or endoscopy. Even after surgery for
CP (e.g. duodenum-preserving pancreatic head resection or drainage operations), repeat surgery can be a viable
and effective option to treat pain relapse. Prior to surgery, though, obstructing stones or anastomotic strictures
should be evaluated on imaging and interdisciplinarily whether they can be addressed in an endoscopic
intervention. Salvage surgery for pain relapse in CP can in most cases be organ-sparing. In cases where organ-
PT
sparing procedures are not possible, total pancreatectomy can be effective option, yet at the cost of postoperative
diabetes.
RI
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
98
Christopher Halloran and Dhiraj Yadav

Q13. What are the indications for referral to a specialist centre for further investigation of
PT
pain?
All patients with presumed or established diagnoses of CP should be routinely referred to
RI
specialist pancreatic centers for investigation and treatment of their pain (quality assessment
moderate; Recommendation: strong; Agreement: strong).
SC
1. Treatment of CP is challenging. It is vital that a systematic and robust approach is
employed. Patients with pain from presumed CP require stepwise evaluation. Many
patients are not referred in a timely fashion to specialist pancreatic or pain services until
U
their pain progressively worsens or has become recalcitrant. The only evidence for
AN
benefit of referral comes from general advice regarding referral to chronic pain
services:
M
a. Referral should be considered when non-specialist management is failing, chronic

pain is poorly controlled, there is significant distress, and/or where specific
specialist intervention or assessment is considered.
D
b. A systematic review of observational studies concluded that longer delays

between specialist referral and specialist consultation result in poorer health and
TE
pain management by the time of this consultation. This deterioration starts as

early as five weeks from referral and there is consensus that a delay of longer than
six months is medically unacceptable(356).
EP
c. No RCT evidence was found that early or late initiation of specific treatments or
early or late specialist referral influences outcome in patients with chronic pain.
C
2. It should be considered whether patients with presumed or established diagnoses of

AC
chronic pancreatitis should be referred to specialist pancreatic centers not only for
metabolic management, but also for assessment of type of pain
(neuropathic/nociceptive/mixed), severity, functional impact and context. This includes
not only assessment of chronic pancreatic pain vs. chronic non-pancreatic abdominal
pain, but also the requirement in such patients to assess their overall pancreatic disease
and to make appropriate management plans. Most importantly to diagnose whether:
a. Primary pancreatic pathology is responsible for the pain.

b. Complications of chronic pancreatitis are responsible for the pain.
ACCEPTED MANUSCRIPT
99
c. Differentiate between a treatable pancreatic conditions as cause of the pain vs. a

chronic pain syndrome without pancreatic disease vs. an alternate diagnosis.
PT
References
1. Yadav D, Lowenfels AB. The Epidemiology of Pancreatitis and Pancreatic Cancer.
RI
Gastroenterology [Internet]. 2013 May [cited 2017 Mar 7];144(6):125261. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/23622135
2. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different
SC
courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis.
Gastroenterology [Internet]. 1994 Nov [cited 2017 Mar 7];107(5):14817. Available from:
3. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic
U
pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients.
Gastroenterology [Internet]. 1984 May [cited 2017 Mar 7];86(5 Pt 1):8208. Available
AN
4. Cavallini G, Frulloni L, Pederzoli P, Talamini G, Bovo P, Bassi C, et al. Long-term
follow-up of patients with chronic pancreatitis in Italy. Scand J Gastroenterol [Internet].
1998 Aug [cited 2017 Mar 7];33(8):8809. Available from:
M
5. Lankisch PG, Lhr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic
pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the
D
disease. Digestion [Internet]. 1993 [cited 2017 Mar 7];54(3):14855. Available from:
TE
6. Wilcox CM, Yadav D, Ye T, Gardner TB, Gelrud A, Sandhu BS, et al. Chronic
pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin
Gastroenterol Hepatol [Internet]. 2015 Mar [cited 2017 Mar 7];13(3):552-60-9. Available
EP
7. Mullady DK, Yadav D, Amann ST, OConnell MR, Barmada MM, Elta GH, et al. Type of
pain, pain-associated complications, quality of life, disability and resource utilisation in
chronic pancreatitis: a prospective cohort study. Gut [Internet]. 2011 Jan 1 [cited 2017
C
Mar 7];60(1):7784. Available from: http://gut.bmj.com/cgi/doi/10.1136/gut.2010.213835

8. Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis.
AC
Gastroenterology [Internet]. 1999 May [cited 2017 Mar 7];116(5):113240. Available

9. Lankisch PG, Seidensticker F, Lhr-Happe A, Otto J, Creutzfeldt W. The course of pain is
the same in alcohol- and nonalcohol-induced chronic pancreatitis. Pancreas [Internet].
10. Takeyama Y. Long-term prognosis of acute pancreatitis in Japan. Clin Gastroenterol
Hepatol [Internet]. 2009 Nov [cited 2017 Mar 7];7(11 Suppl):S15-7. Available from:
11. de las Heras G, de la Pea J, Lpez Arias MJ, Gonzalez-Bernal AC, Martn-Ramos L,
ACCEPTED MANUSCRIPT
100
Pons-Romero F. Drinking habits and pain in chronic pancreatitis. J Clin Gastroenterol

[Internet]. 1995 Jan [cited 2017 Mar 7];20(1):336. Available from:
PT
12. Talamini G, Bassi C, Falconi M, Sartori N, Vaona B, Bovo P, et al. Smoking cessation at
the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas
RI
200711000-00005
13. Olesen SS, Juel J, Nielsen AK, Frkjr JB, Wilder-Smith OHG, Drewes AM. Pain
SC
severity reduces life quality in chronic pancreatitis: Implications for design of future
outcome trials. Pancreatology [Internet]. 2014 Nov [cited 2017 Mar 8];14(6):497502.
14. Machicado JD, Amann ST, Anderson MA, Abberbock J, Sherman S, Conwell DL, et al.
U
Quality of Life in Chronic Pancreatitis is Determined by Constant Pain,
Disability/Unemployment, Current Smoking, and Associated Co-Morbidities. Am J
AN
Gastroenterol [Internet]. 2017 Apr 28 [cited 2017 Jun 21];112(4):63342. Available from:
http://www.nature.com/doifinder/10.1038/ajg.2017.42
15. Woolf CJ. What is this thing called pain? J Clin Invest [Internet]. 2010 Nov 1 [cited 2017
M
Mar 7];120(11):37424. Available from: http://www.jci.org/articles/view/45178

16. Di Sebastiano P, di Mola FF, Di Febbo C, Baccante G, Porreca E, Innocenti P, et al.
Expression of interleukin 8 (IL-8) and substance P in human chronic pancreatitis. Gut
D

17. Friess H, Zhu ZW, di Mola FF, Kulli C, Graber HU, Andren-Sandberg A, et al. Nerve
TE
growth factor and its high-affinity receptor in chronic pancreatitis. Ann Surg [Internet].
1999 Nov [cited 2017 Mar 7];230(5):61524. Available from:
EP
18. Hartel M, di Mola FF, Selvaggi F, Mascetta G, Wente MN, Felix K, et al. Vanilloids in
pancreatic cancer: potential for chemotherapy and pain management. Gut [Internet]. 2006
Apr 1 [cited 2017 Mar 7];55(4):51928. Available from:
C
19. Bchler M, Weihe E, Friess H, Malfertheiner P, Bockman E, Mller S, et al. Changes in

peptidergic innervation in chronic pancreatitis. Pancreas [Internet]. 1992 [cited 2017 Mar
AC

20. Shrikhande S V, Friess H, di Mola FF, Tempia-Caliera A, Conejo Garcia JR, Zhu Z, et al.
NK-1 receptor gene expression is related to pain in chronic pancreatitis. Pain [Internet].
2001 Apr [cited 2017 Mar 7];91(3):20917. Available from:
21. Zhu ZW, Friess H, Wang L, Zimmermann A, Bchler MW. Brain-derived neurotrophic
factor (BDNF) is upregulated and associated with pain in chronic pancreatitis. Dig Dis Sci
[Internet]. 2001 Aug [cited 2017 Mar 7];46(8):16339. Available from:
ACCEPTED MANUSCRIPT
101
22. Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, et al. The
neurotrophic factor artemin influences the extent of neural damage and growth in chronic
PT
23. Abu Dayyeh BK, Conwell D, Buttar NS, Kadilaya V, Hart PA, Baumann NA, et al.
Pancreatic juice prostaglandin e2 concentrations are elevated in chronic pancreatitis and
RI
improve detection of early disease. Clin Transl Gastroenterol [Internet]. 2015 Jan 29 [cited
http://www.nature.com/doifinder/10.1038/ctg.2014.23
SC
24. Pasricha PJ, Jay P. Unraveling the mystery of pain in chronic pancreatitis. Nat Rev
Gastroenterol Hepatol [Internet]. Nature Publishing Group; 2012 Jan 24 [cited 2017 Mar
U
25. Di Sebastiano P, Fink T, Weihe E, Friess H, Innocenti P, Beger HG, et al. Immune cell
infiltration and growth-associated protein 43 expression correlate with pain in chronic
AN
pancreatitis. Gastroenterology [Internet]. 1997 May [cited 2017 Mar 7];112(5):164855.
26. Ceyhan GO, Deucker S, Demir IE, Erkan M, Schmelz M, Bergmann F, et al. Neural
M
fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic
pancreatitis. Lab Invest [Internet]. 2009 Mar 19 [cited 2017 Mar 7];89(3):34761.
Available from: http://www.nature.com/doifinder/10.1038/labinvest.2008.170
D
27. Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, Ramesh H, et al. Mast cell
distribution and activation in chronic pancreatitis. Hum Pathol [Internet]. 2001 Nov [cited
TE
28. Hoogerwerf WA, Gondesen K, Xiao S-Y, Winston JH, Willis WD, Pasricha PJ. The role
of mast cells in the pathogenesis of pain in chronic pancreatitis. BMC Gastroenterol
EP
[Internet]. 2005 Mar 3 [cited 2017 Mar 7];5(1):8. Available from:

http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-5-8
29. Jensen AR, Matzen P, Malchow-Mller A, Christoffersen I. Pattern of pain, duct
morphology, and pancreatic function in chronic pancreatitis. A comparative study. Scand J
C
Gastroenterol [Internet]. 1984 May [cited 2017 Mar 7];19(3):3348. Available from:
AC
30. Ahmed Ali U, Jens S, Busch OR, Keus F, van Goor H, Gooszen HG, et al. Antioxidants
for pain in chronic pancreatitis. In: Ahmed Ali U, editor. Cochrane Database of
Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2014 [cited
2017 Mar 7]. p. CD008945. Available from:
31. Zhu Y, Colak T, Shenoy M, Liu L, Mehta K, Pai R, et al. Transforming growth factor beta
induces sensory neuronal hyperexcitability, and contributes to pancreatic pain and
hyperalgesia in rats with chronic pancreatitis. Mol Pain [Internet]. 2012 Sep 11 [cited
2017 Mar 7];8:65. Available from: http://journals.sagepub.com/doi/10.1186/1744-8069-8-
ACCEPTED MANUSCRIPT
102
65
32. Feng QX, Wang W, Feng XY, Mei XP, Zhu C, Liu ZC, et al. Astrocytic activation in
thoracic spinal cord contributes to persistent pain in rat model of chronic pancreatitis.
PT
Neuroscience [Internet]. 2010 May 5 [cited 2017 Mar 7];167(2):5019. Available from:
33. Liu P-Y, Lu C-L, Wang C-C, Lee I-H, Hsieh J-C, Chen C-C, et al. Spinal microglia
RI
initiate and maintain hyperalgesia in a rat model of chronic pancreatitis. Gastroenterology
[Internet]. 2012 Jan [cited 2017 Mar 7];142(1):165173.e2. Available from:
SC
34. Vera-Portocarrero LP, Xie JY, Yie JX, Kowal J, Ossipov MH, King T, et al. Descending
facilitation from the rostral ventromedial medulla maintains visceral pain in rats with
experimental pancreatitis. Gastroenterology [Internet]. 2006 Jun [cited 2017 Mar
7];130(7):215564. Available from:
U
35. Bouwense SAW, Olesen SS, Drewes AM, Frkjr JB, van Goor H, Wilder-Smith OHG.
AN
Is altered central pain processing related to disease stage in chronic pancreatitis patients
with pain? An exploratory study. Milanese S, editor. PLoS One [Internet]. 2013 Feb 6
[cited 2017 Mar 7];8(2):e55460. Available from:
M
http://dx.plos.org/10.1371/journal.pone.0055460
36. Dimcevski G, Sami SAK, FunchJensen P, Le Pera D, Valeriani M, ArendtNielsen L, et
al. Pain in Chronic Pancreatitis: The Role of Reorganization in the Central Nervous
D
System. Gastroenterology [Internet]. 2007 Apr [cited 2017 Mar 13];132(4):154656.

37. Buscher HCJL, Wilder-Smith OHG, van Goor H. Chronic pancreatitis patients show
TE
hyperalgesia of central origin: a pilot study. Eur J Pain [Internet]. 2006 May [cited 2017
Mar 7];10(4):36370. Available from: http://doi.wiley.com/10.1016/j.ejpain.2005.06.006
38. Olesen SS, Brock C, Krarup AL, Funch-Jensen P, Arendt-Nielsen L, Wilder-Smith OH, et
EP
al. Descending inhibitory pain modulation is impaired in patients with chronic

pancreatitis. Clin Gastroenterol Hepatol [Internet]. 2010 Aug [cited 2017 Mar
C
39. Olesen SS, Frkjr JB, Lelic D, Valeriani M, Drewes AM. Pain-associated adaptive
cortical reorganisation in chronic pancreatitis. Pancreatology [Internet]. 2010 Mar [cited
AC

40. Olesen SS, Hansen TM, Graversen C, Steimle K, Wilder-Smith OHG, Drewes AM.
Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal
cerebral pain processing? Eur J Gastroenterol Hepatol [Internet]. 2011 May [cited 2017
201105000-00008
41. de Vries M, Wilder-Smith OH, Jongsma M LA, van den Broeke EN, Arns M, van Goor H,
ACCEPTED MANUSCRIPT
103
et al. Altered resting state EEG in chronic pancreatitis patients: toward a marker for
chronic pain. J Pain Res [Internet]. 2013 Nov 25 [cited 2017 Mar 7];6:81524. Available
from: http://www.dovepress.com/altered-resting-state-eeg-in-chronic-pancreatitis-
PT
patients-toward-a-ma-peer-reviewed-article-JPR
42. Ceyhan GO, Bergmann F, Kadihasanoglu M, Altintas B, Demir IE, Hinz U, et al.
Pancreatic neuropathy and neuropathic pain--a comprehensive pathomorphological study
RI
of 546 cases. Gastroenterology [Internet]. 2009 Jan [cited 2017 Mar 7];136(1):177
43. Frokjaer JB, Olesen SS, Gram M, Yavarian Y, Bouwense SAW, Wilder-Smith OHG, et
SC
al. Altered brain microstructure assessed by diffusion tensor imaging in patients with
chronic pancreatitis. Gut [Internet]. 2011 Nov 1 [cited 2017 Mar 7];60(11):155462.
Available from: http://gut.bmj.com/cgi/doi/10.1136/gut.2010.236620
44. Turk DC MR. Handbook of pain assessment. 2nd ed. New York: Guilford Press; 2001.
U
45. Turk DC MR. The measurement of pain and the assessment of people experiencing pain.
In: Handbook of Pain Assessment. 2nd ed. New York: Guilford Press; 2201. p. 311.
AN
46. Dworkin RH, Turk DC, Peirce-Sandner S, Baron R, Bellamy N, Burke LB, et al. Research
design considerations for confirmatory chronic pain clinical trials: IMMPACT
recommendations. Pain [Internet]. 2010 May [cited 2017 Mar 7];149(2):17793.
M

47. Goulden MR. The pain of chronic pancreatitis: a persistent clinical challenge. Br J Pain
[Internet]. 2013 Feb [cited 2017 Mar 7];7(1):822. Available from:
D
48. Max MB. Towards physiologically based treatment of patients with neuropathic pain. Pain
[Internet]. 1990 Aug [cited 2017 Mar 7];42(2):1317. Available from:
TE
49. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, et al. Towards a
mechanism-based classification of pain? Pain [Internet]. 1998 Sep [cited 2017 Mar
EP

50. Merskey H BN. Classification of chronic pain. 2 ed. Seattle: IASP Press; 1994.
51. Dalton JA, McNaull F. A call for standardizing the clinical rating of pain intensity using a
0 to 10 rating scale. Cancer Nurs [Internet]. 1998 Feb [cited 2017 Mar 7];21(1):469.
C

52. Axon AT. Endoscopic retrograde cholangiopancreatography in chronic pancreatitis.
AC
Cambridge classification. Radiol Clin North Am [Internet]. 1989 Jan [cited 2017 Mar
53. Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive
review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology,
and clinical features. Dis Mon [Internet]. 2014 Dec [cited 2017 Mar 7];60(12):53050.
54. Balliet WE, Edwards-Hampton S, Borckardt JJ, Morgan K, Adams D, Owczarski S, et al.
Depressive Symptoms, Pain, and Quality of Life among Patients with Nonalcohol-Related
Chronic Pancreatitis. Pain Res Treat [Internet]. 2012 [cited 2017 Mar 13];2012:978646.
ACCEPTED MANUSCRIPT
104
Available from: http://www.hindawi.com/journals/prt/2012/978646/

55. Edwards RR, Bingham CO, Bathon J, Haythornthwaite JA. Catastrophizing and pain in
arthritis, fibromyalgia, and other rheumatic diseases. Arthritis Rheum [Internet]. 2006 Apr
PT
15 [cited 2017 Mar 7];55(2):32532. Available from:
56. Jensen MP, Ehde DM, Hoffman AJ, Patterson DR, Czerniecki JM, Robinson LR.
RI
Cognitions, coping and social environment predict adjustment to phantom limb pain. Pain
[Internet]. 2002 Jan [cited 2017 Mar 7];95(12):13342. Available from:
SC
57. Richardson C, Glenn S, Horgan M, Nurmikko T. A prospective study of factors associated
with the presence of phantom limb pain six months after major lower limb amputation in
patients with peripheral vascular disease. J Pain [Internet]. 2007 Oct [cited 2017 Mar
U
58. Picavet HSJ, Vlaeyen JWS, Schouten JSAG. Pain catastrophizing and kinesiophobia:
AN
predictors of chronic low back pain. Am J Epidemiol [Internet]. 2002 Dec 1 [cited 2017
M
59. Karels CH, Bierma-Zeinstra SMA, Burdorf A, Verhagen AP, Nauta AP, Koes BW. Social
and psychological factors influenced the course of arm, neck and shoulder complaints. J
Clin Epidemiol [Internet]. 2007 Aug [cited 2017 Mar 7];60(8):83948. Available from:
D
60. Voerman GE, Sandsj L, Vollenbroek-Hutten MMR, Larsman P, Kadefors R, Hermens
HJ. Changes in cognitive-behavioral factors and muscle activation patterns after
TE
interventions for work-related neck-shoulder complaints: relations with discomfort and

disability. J Occup Rehabil [Internet]. 2007 Dec 13 [cited 2017 Mar 7];17(4):593609.
Available from: http://link.springer.com/10.1007/s10926-007-9109-9
EP
61. Hill JC, Lewis M, Sim J, Hay EM, Dziedzic K. Predictors of poor outcome in patients
with neck pain treated by physical therapy. Clin J Pain [Internet]. 2007 Oct [cited 2017
C
200710000-00007
62. Lozano Caldern SA, Paiva A, Ring D. Patient satisfaction after open carpal tunnel
AC
release correlates with depression. J Hand Surg Am [Internet]. 2008 Mar [cited 2017 Mar
63. Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of
postoperative pain intensity: a prospective study. Clin J Pain [Internet]. [cited 2017 Mar
64. Strulov L, Zimmer EZ, Granot M, Tamir A, Jakobi P, Lowenstein L. Pain catastrophizing,
response to experimental heat stimuli, and post-cesarean section pain. J Pain [Internet].
2007 Mar [cited 2017 Mar 7];8(3):2739. Available from:
ACCEPTED MANUSCRIPT
105
65. Jacobsen PB, Butler RW. Relation of cognitive coping and catastrophizing to acute pain
and analgesic use following breast cancer surgery. J Behav Med [Internet]. 1996 Feb
PT
66. Kendell K, Saxby B, Farrow M, Naisby C. Psychological factors associated with short-
RI
term recovery from total knee replacement. Br J Health Psychol [Internet]. 2001 Feb
[cited 2017 Mar 7];6(Pt 1):4152. Available from:
http://doi.wiley.com/10.1348/135910701169043
SC
67. Samwel H, Slappendel R, Crul BJ, Voerman VF. Psychological predictors of the
effectiveness of radiofrequency lesioning of the cervical spinal dorsal ganglion (RF-
DRG). Eur J Pain [Internet]. 2000 Jun [cited 2017 Mar 7];4(2):14955. Available from:
http://doi.wiley.com/10.1053/eujp.2000.0165
U
68. Frkjr JB, Olesen SS, Gram M, Yavarian Y, Bouwense SAW, Wilder-Smith OHG, et al.
Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic
AN
pancreatitis. Gut [Internet]. 2011 Nov 1 [cited 2017 Mar 13];60(11):155462. Available
from: http://gut.bmj.com/cgi/doi/10.1136/gut.2010.236620
69. Campbell CM, Bounds SC, Kuwabara H, Edwards RR, Campbell JN, Haythornthwaite
M
JA, et al. individual variation in sleep quality and duration is related to cerebral mu opioid
receptor binding potential during tonic laboratory pain in healthy subjects. Pain Med
[Internet]. 2013 Dec 1 [cited 2017 Mar 13];14(12):188292. Available from:
D
https://academic.oup.com/painmedicine/article-lookup/doi/10.1111/pme.12231
70. Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path
forward. J Pain [Internet]. 2013 Dec [cited 2017 Mar 13];14(12):153952. Available from:
TE
71. Fitzsimmons D, Kahl S, Butturini G, van Wyk M, Bornman P, Bassi C, et al. Symptoms
and quality of life in chronic pancreatitis assessed by structured interview and the EORTC
EP
QLQ-C30 and QLQ-PAN26. Am J Gastroenterol [Internet]. 2005 Apr [cited 2017 Mar
7];100(4):91826. Available from: http://www.nature.com/doifinder/10.1111/j.1572-
0241.2005.40859.x
72. Kuner R. Central mechanisms of pathological pain. Nat Med [Internet]. 2010 Nov 14
C

AC
73. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain
[Internet]. 2011 Mar [cited 2017 Mar 7];152(Supplement):S215. Available from:
74. Woolf CJ. What to call the amplification of nociceptive signals in the central nervous
system that contribute to widespread pain? Pain [Internet]. 2014 Oct [cited 2017 Mar
7];155(10):19112. Available from:
201410000-00002
75. Fregni F, Pascual-Leone A, Freedman SD. Pain in Chronic Pancreatitis: A Salutogenic
ACCEPTED MANUSCRIPT
106
Mechanism or a Maladaptive Brain Response? Pancreatology [Internet]. 2007 Oct [cited

PT
76. Rattner DW, Fernandez-del Castillo C, Warshaw AL. Pitfalls of distal pancreatectomy for
relief of pain in chronic pancreatitis. Am J Surg [Internet]. 1996 Jan [cited 2017 Mar
7];171(1):142-5-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8554129
RI
77. Fink R. Pain assessment: the cornerstone to optimal pain management. Proc (Bayl Univ
Med Cent) [Internet]. 2000 Jul [cited 2017 Mar 7];13(3):2369. Available from:
SC
78. Bloechle C, Izbicki JR, Knoefel WT, Kuechler T, Broelsch CE. Quality of life in chronic
pancreatitis--results after duodenum-preserving resection of the head of the pancreas.
Pancreas [Internet]. 1995 Jul [cited 2017 Mar 7];11(1):7785. Available from:
U
79. Marco CA, Nagel J, Klink E, Baehren D. Factors associated with self-reported pain scores
among ED patients. Am J Emerg Med [Internet]. 2012 Feb [cited 2017 Mar 7];30(2):331
AN
7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21367555
80. Seicean A, Grigorescu M, Tanu M, Dumitracu DL, Pop D, Mocan T. Pain in chronic
pancreatitis: assessment and relief through treatment. Rom J Gastroenterol [Internet]. 2004
M
Mar [cited 2017 Mar 7];13(1):915. Available from:

81. Gracely RH. Pain measurement. Acta Anaesthesiol Scand [Internet]. 1999 Oct [cited 2017
D

82. Edwards RR, Fillingim RB. Ethnic differences in thermal pain responses. Psychosom Med
[Internet]. [cited 2017 Mar 7];61(3):34654. Available from:
TE
83. Fillingim RB, Edwards RR, Powell T. The relationship of sex and clinical pain to
experimental pain responses. Pain [Internet]. 1999 Dec [cited 2017 Mar 7];83(3):41925.
EP

84. Edwards RR, Fillingim RB. Effects of age on temporal summation and habituation of
thermal pain: clinical relevance in healthy older and younger adults. J Pain [Internet].
C
85. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse
AC
noxious inhibitory controls (DNIC): association with clinical variables. Pain [Internet].
86. Olesen SS, van Goor H, Bouwense SAW, Wilder-Smith OHG, Drewes AM. Reliability of
static and dynamic quantitative sensory testing in patients with painful chronic
pancreatitis. Reg Anesth Pain Med [Internet]. 2012 [cited 2017 Mar 7];37(5):5306.
Available from:
201209000-00014
ACCEPTED MANUSCRIPT
107
87. Granovsky Y, Yarnitsky D. Personalized pain medicine: the clinical value of

psychophysical assessment of pain modulation profile. Rambam Maimonides Med J
[Internet]. 2013 Oct 29 [cited 2017 Mar 7];4(4):e0024. Available from:
PT
http://www.rmmj.org.il/(S(sef2mr2er5p4lsb3kefhcwa0))/Pages/Article.aspx?manuId=336
88. Melzack R, Coderre TJ, Katz J, Vaccarino AL. Central neuroplasticity and pathological
pain. Ann N Y Acad Sci [Internet]. 2001 Mar [cited 2017 Mar 7];933:15774. Available
RI
89. Melzack R. Pain and the neuromatrix in the brain. J Dent Educ [Internet]. 2001 Dec [cited
SC
90. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of
pain. Curr Opin Support Palliat Care [Internet]. 2014 Jun [cited 2017 Mar 7];8(2):14351.
Available from:
U
201503000-00008
AN
91. Edwards RR, Doleys DM, Lowery D, Fillingim RB. Pain tolerance as a predictor of
outcome following multidisciplinary treatment for chronic pain: differential effects as a
function of sex. Pain [Internet]. 2003 Dec [cited 2017 Mar 7];106(3):41926. Available
M
92. Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early
pain after laparoscopic cholecystectomy. Pain [Internet]. 2001 Feb 15 [cited 2017 Mar
D

93. Werner MU, Duun P, Kehlet H. Prediction of postoperative pain by preoperative
nociceptive responses to heat stimulation. Anesthesiology [Internet]. 2004 Jan [cited 2017
TE
Mar 7];100(1):1159; discussion 5A. Available from:

94. Granot M, Zimmer EZ, Friedman M, Lowenstein L, Yarnitsky D. Association between
EP
quantitative sensory testing, treatment choice, and subsequent pain reduction in vulvar
vestibulitis syndrome. J Pain [Internet]. 2004 May [cited 2017 Mar 7];5(4):22632.
95. Hsu Y-W, Somma J, Hung Y-C, Tsai P-S, Yang C-H, Chen C-C. Predicting postoperative
C
pain by preoperative pressure pain assessment. Anesthesiology [Internet]. 2005 Sep [cited
AC
96. Soyupek S, Bozlu M, Armaan A, Ozorak A, Perk H. Does experimental pain assessment
before biopsy predict for pain during transrectal ultrasound-guided prostate biopsy?
Urology [Internet]. 2007 Oct [cited 2017 Mar 7];70(4):6814. Available from:
97. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ. Postcesarean section pain
prediction by preoperative experimental pain assessment. Anesthesiology [Internet]. 2003
Jun [cited 2017 Mar 7];98(6):14226. Available from:
ACCEPTED MANUSCRIPT
108
98. Nielsen PR, Nrgaard L, Rasmussen LS, Kehlet H. Prediction of post-operative pain by an
electrical pain stimulus. Acta Anaesthesiol Scand [Internet]. 2007 May [cited 2017 Mar
7];51(5):5826. Available from: http://doi.wiley.com/10.1111/j.1399-6576.2007.01271.x
PT
99. Geiss A, Rohleder N, Kirschbaum C, Steinbach K, Bauer HW, Anton F. Predicting the
failure of disc surgery by a hypofunctional HPA axis: evidence from a prospective study
on patients undergoing disc surgery. Pain [Internet]. 2005 Mar [cited 2017 Mar 7];114(1
RI
2):10417. Available from:
200503000-00013
SC
100. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, et al.
Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at
risk. Pain [Internet]. 2008 Aug 15 [cited 2017 Mar 7];138(1):228. Available from:
U
200808150-00006
101. Lundblad H, Kreicbergs A, Jansson KA. Prediction of persistent pain after total knee
AN
replacement for osteoarthritis. J Bone Joint Surg Br [Internet]. 2008 Feb 1 [cited 2017 Mar
http://www.bjj.boneandjoint.org.uk/cgi/doi/10.1302/0301-620X.90B2.19640
M
102. Edwards RR, Haythornthwaite JA, Tella P, Max MB, Raja S. Basal heat pain thresholds
predict opioid analgesia in patients with postherpetic neuralgia. Anesthesiology [Internet].
2006 Jun [cited 2017 Mar 7];104(6):12438. Available from:
D
103. Bouwense SAW, de Vries M, Schreuder LTW, Olesen SS, Frkjr JB, Drewes AM, et al.
Systematic mechanism-orientated approach to chronic pancreatitis pain. World J
TE
Gastroenterol [Internet]. 2015 Jan 7 [cited 2017 Mar 13];21(1):4759. Available from:
104. Dimcevski G, Schipper KP, Tage-Jensen U, Funch-Jensen P, Krarup AL, Toft E, et al.
EP
Hypoalgesia to experimental visceral and somatic stimulation in painful chronic

pancreatitis. Eur J Gastroenterol Hepatol [Internet]. 2006 Jul [cited 2017 Mar
C
200607000-00010
105. Dimcevski G, Staahl C, Andersen SD, Thorsgaard N, Funch-Jensen P, Arendt-Nielsen L,
AC
et al. Assessment of experimental pain from skin, muscle, and esophagus in patients with
chronic pancreatitis. Pancreas [Internet]. 2007 Jul [cited 2017 Mar 7];35(1):229.
Available from:
200707000-00003
106. Drewes AM, Gratkowski M, Sami SAK, Dimcevski G, Funch-Jensen P, Arendt-Nielsen
L. Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies
during experimental pain. World J Gastroenterol [Internet]. 2008 Jul 7 [cited 2017 Mar
ACCEPTED MANUSCRIPT
109
107. Olesen SS, Graversen C, Bouwense SAW, van Goor H, Wilder-Smith OHG, Drewes AM.
Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.
Miaskowski C, editor. PLoS One [Internet]. 2013 Mar 1 [cited 2017 Mar 7];8(3):e57963.
PT
Available from: http://dx.plos.org/10.1371/journal.pone.0057963
108. Bouwense SAW, Olesen SS, Drewes AM, Poley J-W, van Goor H, Wilder-Smith OHG.
Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a
RI
randomized, controlled trial. Eldabe S, editor. PLoS One [Internet]. 2012 Aug 6 [cited
SC
109. Bouwense SAW, Buscher HCJL, van Goor H, Wilder-Smith OHG. S-ketamine modulates
hyperalgesia in patients with chronic pancreatitis pain. Reg Anesth Pain Med [Internet].
U
201105000-00019
110. Staahl C, Dimcevski G, Andersen SD, Thorsgaard N, Christrup LL, Arendt-Nielsen L, et
AN
al. Differential effect of opioids in patients with chronic pancreatitis: an experimental pain
study. Scand J Gastroenterol [Internet]. 2007 Mar 8 [cited 2017 Mar 7];42(3):38390.
M
111. Ceyhan GO, Michalski CW, Demir IE, Mller MW, Friess H. Pancreatic pain. Best Pract
Res Clin Gastroenterol [Internet]. 2008 Feb [cited 2017 Mar 7];22(1):3144. Available
D
112. Birklein F, Sommer C. Pain: Quantitative sensory testing--a tool for daily practice? Nat
Rev Neurol [Internet]. 2013 Sep 6 [cited 2017 Mar 7];9(9):4902. Available from:
http://www.nature.com/doifinder/10.1038/nrneurol.2013.157
TE
113. Haussleiter IS, Richter H, Scherens A, Schwenkreis P, Tegenthoff M, Maier C.

NeuroQuick - A novel bedside test for small fiber neuropathy? Eur J Pain [Internet]. 2008
Nov [cited 2017 Mar 7];12(8):10007. Available from:
EP
114. Osgood E, Trudeau JJ, Eaton TA, Jensen MP, Gammaitoni A, Simon LS, et al.
Development of a bedside pain assessment kit for the classification of patients with
osteoarthritis. Rheumatol Int [Internet]. 2015 Jun 16 [cited 2017 Mar 7];35(6):100513.
C
Available from: http://link.springer.com/10.1007/s00296-014-3191-z

115. Samokhvalov A V, Rehm J, Roerecke M. Alcohol Consumption as a Risk Factor for
AC
Acute and Chronic Pancreatitis: A Systematic Review and a Series of Meta-analyses.

EBioMedicine [Internet]. 2015 Dec [cited 2017 Mar 7];2(12):19962002. Available from:
116. Pelli H, Sand J, Laippala P, Nordback I. Long-term follow-up after the first episode of
acute alcoholic pancreatitis: time course and risk factors for recurrence. Scand J
Gastroenterol [Internet]. 2000 May [cited 2017 Mar 7];35(5):5525. Available from:
117. Gullo L, Migliori M, Pezzilli R, Olh A, Farkas G, Levy P, et al. An update on recurrent
acute pancreatitis: data from five European countries. Am J Gastroenterol [Internet]. 2002
ACCEPTED MANUSCRIPT
110
Aug [cited 2017 Mar 7];97(8):195962. Available from:

http://www.nature.com/doifinder/10.1111/j.1572-0241.2002.05907.x
118. Lund H, Tnnesen H, Tnnesen MH, Olsen O. Long-term recurrence and death rates after
PT
acute pancreatitis. Scand J Gastroenterol [Internet]. 2006 Feb 8 [cited 2017 Mar
http://www.tandfonline.com/doi/full/10.1080/00365520510024133
RI
119. Pelli H, Lappalainen-Lehto R, Piironen A, Sand J, Nordback I. Risk factors for recurrent
acute alcohol-associated pancreatitis: A prospective analysis. Scand J Gastroenterol
[Internet]. 2008 Jan 8 [cited 2017 Mar 7];43(5):61421. Available from:
SC
120. Nordback I, Pelli H, Lappalainen-Lehto R, Jrvinen S, Rty S, Sand J. The recurrence of
acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial.
Gastroenterology [Internet]. 2009 Mar [cited 2017 Mar 7];136(3):84855. Available from:
U
121. Nikkola J, Rty S, Laukkarinen J, Seppnen H, Lappalainen-Lehto R, Jrvinen S, et al.
AN
Abstinence after first acute alcohol-associated pancreatitis protects against recurrent
pancreatitis and minimizes the risk of pancreatic dysfunction. Alcohol Alcohol [Internet].
2013 Jul 1 [cited 2017 Mar 7];48(4):4836. Available from:
M
https://academic.oup.com/alcalc/article-lookup/doi/10.1093/alcalc/agt019
122. Mirijello A, DAngelo C, Ferrulli A, Vassallo G, Antonelli M, Caputo F, et al.
Identification and management of alcohol withdrawal syndrome. Drugs [Internet]. 2015
D
Mar 10 [cited 2017 Mar 7];75(4):35365. Available from:

123. Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol
TE
withdrawal syndrome. J Clin Pharm Ther [Internet]. 2010 Apr [cited 2017 Mar
7];35(2):15367. Available from: http://doi.wiley.com/10.1111/j.1365-2710.2009.01098.x
124. Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. In:
EP
Minozzi S, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK:

John Wiley & Sons, Ltd; 2010 [cited 2017 Mar 7]. p. CD005064. Available from:
125. Volpicelli JR, Alterman AI, Hayashida M, OBrien CP. Naltrexone in the treatment of
C
alcohol dependence. Arch Gen Psychiatry [Internet]. 1992 Nov [cited 2017 Mar
AC
126. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al.
Pharmacotherapy for Adults With Alcohol Use Disorders in Outpatient Settings. Jama
[Internet]. 2014;311(7110):1889. Available from:
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.3628%5Cnhttp://jama.j
amanetwork.com/article.aspx?articleid=1869208
127. Anton RF, OMalley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al.
Combined pharmacotherapies and behavioral interventions for alcohol dependence: the
COMBINE study: a randomized controlled trial. JAMA [Internet]. 2006 May 3 [cited
ACCEPTED MANUSCRIPT
111
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.295.17.2003
128. Anton RF, Oroszi G, OMalley S, Couper D, Swift R, Pettinati H, et al. An evaluation of
mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of
PT
alcohol dependence: results from the Combined Pharmacotherapies and Behavioral
Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry
RI
http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.65.2.135
129. Donovan DM, Anton RF, Miller WR, Longabaugh R, Hosking JD, youngblood M.
Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (The
SC
COMBINE Study): Examination of Posttreatment Drinking Outcomes. J Stud Alcohol
Drugs [Internet]. 2008 Jan [cited 2017 Mar 7];69(1):513. Available from:
http://www.jsad.com/doi/10.15288/jsad.2008.69.5
130. Mutschler J, Grosshans M, Soyka M, Rsner S. Current Findings and Mechanisms of
U
Action of Disulfiram in the Treatment of Alcohol Dependence. Pharmacopsychiatry
[Internet]. 2016 Jul 17 [cited 2017 Mar 7];49(4):13741. Available from:
AN
http://www.thieme-connect.de/DOI/DOI?10.1055/s-0042-103592
131. Litten RZ, Wilford BB, Falk DE, Ryan ML, Fertig JB. Potential medications for the
treatment of alcohol use disorder: An evaluation of clinical efficacy and safety. Subst
M
Abus [Internet]. 2016 Apr 2 [cited 2017 Mar 7];37(2):28698. Available from:
http://www.tandfonline.com/doi/full/10.1080/08897077.2015.1133472
132. Modesto-Lowe V, Kranzler HR. Diagnosis and treatment of alcohol-dependent patients
D
with comorbid psychiatric disorders. Alcohol Res Health [Internet]. 1999 [cited 2017 Mar
133. Kranzler HR, Rosenthal RN. Dual diagnosis: alcoholism and co-morbid psychiatric
TE
disorders. Am J Addict [Internet]. 2003 [cited 2017 Mar 7];12 Suppl 1:S26-40. Available
134. Di Sclafani V, Finn P, Fein G. Treatment-naive active alcoholics have greater psychiatric
EP
comorbidity than normal controls but less than treated abstinent alcoholics. Drug Alcohol
Depend [Internet]. 2008 Nov 1 [cited 2017 Mar 7];98(12):11522. Available from:
135. Starosta AN, Leeman RF, Volpicelli JR. The BRENDA model: integrating psychosocial
C
treatment and pharmacotherapy for the treatment of alcohol use disorders. J Psychiatr
Pract [Internet]. 2006 Mar [cited 2017 Mar 7];12(2):809. Available from:
AC
136. Magill M, Kiluk BD, McCrady BS, Tonigan JS, Longabaugh R. Active Ingredients of
Treatment and Client Mechanisms of Change in Behavioral Treatments for Alcohol Use
Disorders: Progress 10 Years Later. Alcohol Clin Exp Res [Internet]. 2015 Oct [cited
2017 Mar 7];39(10):185262. Available from: http://doi.wiley.com/10.1111/acer.12848
137. Khan A, Tansel A, White DL, Kayani WT, Bano S, Lindsay J, et al. Efficacy of
Psychosocial Interventions in Inducing and Maintaining Alcohol Abstinence in Patients
With Chronic Liver Disease: A Systematic Review. Clin Gastroenterol Hepatol [Internet].
2016 Feb [cited 2017 Mar 7];14(2):191202.e14; quiz e20. Available from:
ACCEPTED MANUSCRIPT
112
138. Ferri M, Amato L, Davoli M. Alcoholics Anonymous and other 12-step programmes for
alcohol dependence. Ferri M, editor. Cochrane database Syst Rev [Internet]. Chichester,
PT
UK: John Wiley & Sons, Ltd; 2006 Jul 19 [cited 2017 Mar 7];(3):CD005032. Available
from: http://doi.wiley.com/10.1002/14651858.CD005032.pub2
139. Yuhara H, Ogawa M, Kawaguchi Y, Igarashi M, Mine T. Smoking and risk for acute
RI
pancreatitis: a systematic review and meta-analysis. Pancreas [Internet]. 2014 Nov [cited
SC
201411000-00012
140. Sun X, Huang X, Zhao R, Chen B, Xie Q. Meta-analysis: Tobacco smoking may enhance
the risk of acute pancreatitis. Pancreatology [Internet]. 2015 May [cited 2017 Mar
U
http://linkinghub.elsevier.com/retrieve/pii/S142439031500040X
141. Alexandre M, Pandol SJ, Gorelick FS, Thrower EC. The emerging role of smoking in the
AN
development of pancreatitis. Pancreatology [Internet]. 2011 Jan [cited 2017 Mar
M
142. Edderkaoui M, Thrower E. Smoking and Pancreatic Disease. J Cancer Ther [Internet].
2013 Nov 1 [cited 2017 Mar 7];4(10A):3440. Available from:
http://www.scirp.org/journal/PaperDownload.aspx?DOI=10.4236/jct.2013.410A005
D
143. Ye X, Lu G, Huai J, Ding J. Impact of smoking on the risk of pancreatitis: a systematic

review and meta-analysis. Katoh M, editor. PLoS One [Internet]. 2015 Apr 16 [cited 2017
TE
144. Lin Y, Tamakoshi A, Hayakawa T, Ogawa M, Ohno Y. Cigarette smoking as a risk factor
for chronic pancreatitis: a case-control study in Japan. Research Committee on Intractable
Pancreatic Diseases. Pancreas [Internet]. 2000 Aug [cited 2017 Mar 7];21(2):10914.
EP

145. Tolstrup JS, Kristiansen L, Becker U, Gronbaek M. Smoking and risk of acute and chronic
pancreatitis among women and men: a population-based cohort study. Arch Intern Med.
2009 Mar;169(6):6039.
C
146. Andriulli A, Botteri E, Almasio PL, Vantini I, Uomo G, Maisonneuve P, et al. Smoking as
a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas [Internet]. 2010
AC
Nov [cited 2017 Mar 13];39(8):120510. Available from:

201011000-00014
147. Petre B, Torbey S, Griffith JW, De Oliveira G, Herrmann K, Mansour A, et al. Smoking
increases risk of pain chronification through shared corticostriatal circuitry. Hum Brain
Mapp [Internet]. 2015 Feb [cited 2017 Jun 21];36(2):68394. Available from:
http://doi.wiley.com/10.1002/hbm.22656
148. Ditre JW, Kosiba JD, Zale EL, Zvolensky MJ, Maisto SA. Chronic Pain Status, Nicotine
Withdrawal, and Expectancies for Smoking Cessation Among Lighter Smokers. Ann
ACCEPTED MANUSCRIPT
113
Behav Med [Internet]. 2016 Jun 26 [cited 2017 Jun 21];50(3):42735. Available from:
149. Han S, Kheder J, Bocelli L, Fahed J, Wachholtz A, Seward G, et al. Smoking Cessation in
PT
a Chronic Pancreatitis Population. Pancreas [Internet]. 2016 Oct [cited 2017 Jun
RI
201610000-00011
150. Maisonneuve P. Cigarette smoking accelerates progression of alcoholic chronic
SC
151. Chowdhury P, MacLeod S, Udupa KB, Rayford PL. Pathophysiological effects of nicotine
on the pancreas: an update. Exp Biol Med (Maywood) [Internet]. 2002 Jul [cited 2017
U
152. Sadr-Azodi O, Andrn-Sandberg , Orsini N, Wolk A. Cigarette smoking, smoking
cessation and acute pancreatitis: a prospective population-based study. Gut [Internet].
AN
2012 Feb [cited 2017 Mar 7];61(2):2627. Available from:
http://gut.bmj.com/lookup/doi/10.1136/gutjnl-2011-300566
153. Mooney ME, Schmitz JM, Allen S, Grabowski J, Pentel P, Oliver A, et al. Bupropion and
M
naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical

trial. Clin Pharmacol Ther [Internet]. 2016 Oct [cited 2017 Mar 7];100(4):34452.
Available from: http://doi.wiley.com/10.1002/cpt.402
D
154. Ebbert JO, Hughes JR, West RJ, Rennard SI, Russ C, McRae TD, et al. Effect of
Varenicline on Smoking Cessation Through Smoking Reduction. JAMA [Internet]. 2015
Feb 17 [cited 2017 Mar 7];313(7):687. Available from:
TE
155. Tulloch HE, Pipe AL, Els C, Clyde MJ, Reid RD. Flexible, dual-form nicotine
replacement therapy or varenicline in comparison with nicotine patch for smoking
EP
cessation: a randomized controlled trial. BMC Med [Internet]. 2016 Jun 7 [cited 2017 Mar
http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0626-2
156. Erwin BL, Slaton RM. Varenicline in the treatment of alcohol use disorders. Ann
C
Pharmacother [Internet]. 2014 Nov [cited 2017 Mar 7];48(11):144555. Available from:
http://journals.sagepub.com/doi/10.1177/1060028014545806
AC
157. de Bejczy A, Lf E, Walther L, Guterstam J, Hammarberg A, Asanovska G, et al.

Varenicline for treatment of alcohol dependence: a randomized, placebo-controlled trial.
Alcohol Clin Exp Res [Internet]. 2015 Nov [cited 2017 Mar 7];39(11):218999. Available
from: http://doi.wiley.com/10.1111/acer.12854
158. Vogeler T, McClain C, Evoy KE. Combination bupropion SR and varenicline for smoking
cessation: a systematic review. Am J Drug Alcohol Abuse [Internet]. 2016 Mar 3 [cited
159. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking
ACCEPTED MANUSCRIPT
114
cessation: an overview and network meta-analysis. Cahill K, editor. Cochrane database

Syst Rev [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2013 May 31 [cited 2017
Mar 7];(5):CD009329. Available from:
PT
160. Iliceto P, Fino E, Pasquariello S, DAngelo Di Paola ME, Enea D. Predictors of success in
smoking cessation among Italian adults motivated to quit. J Subst Abuse Treat [Internet].
RI
161. Vidrine JI, Spears CA, Heppner WL, Reitzel LR, Marcus MT, Cinciripini PM, et al.
SC
Efficacy of mindfulness-based addiction treatment (MBAT) for smoking cessation and
lapse recovery: A randomized clinical trial. J Consult Clin Psychol [Internet]. 2016 Sep
http://doi.apa.org/getdoi.cfm?doi=10.1037/ccp0000117
U
162. Roberts DL, Cannon KJ, Wellik KE, Wu Q, Budavari AI. Burnout in inpatient-based
versus outpatient-based physicians: a systematic review and meta-analysis. J Hosp Med
AN
http://www.journalofhospitalmedicine.com/jhospmed/article/128086/physician-burnout-
meta-analysis
M
163. Owyang C, Louie DS, Tatum D. Feedback regulation of pancreatic enzyme secretion.
Suppression of cholecystokinin release by trypsin. J Clin Invest [Internet]. 1986 Jun 1
D
http://www.jci.org/articles/view/112534
164. Mssner J, Wresky HP, Kestel W, Zeeh J, Regner U, Fischbach W. Influence of treatment
with pancreatic extracts on pancreatic enzyme secretion. Gut [Internet]. 1989 Aug [cited
TE

165. Krawisz BR, Miller LJ, DiMagno EP, Go VL. In the absence of nutrients, pancreatic-
EP
biliary secretions in the jejunum do not exert feedback control of human pancreatic or
gastric function. J Lab Clin Med [Internet]. 1980 Jan [cited 2017 Mar 7];95(1):138.
166. Warshaw AL, Banks PA, Fernndez-Del Castillo C. AGA technical review: treatment of
C
pain in chronic pancreatitis. Gastroenterology [Internet]. 1998 Sep [cited 2017 Mar
AC
167. Slaff J, Jacobson D, Tillman CR, Curington C, Toskes P. Protease-specific suppression of

pancreatic exocrine secretion. Gastroenterology [Internet]. 1984 Jul [cited 2017 Mar
168. Braganza JM. A framework for the aetiogenesis of chronic pancreatitis. Digestion
[Internet]. 1998 [cited 2017 Mar 7];59 Suppl 4:112. Available from:
169. Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy
in patients with chronic pancreatitis. Scand J Gastroenterol [Internet]. 1986 Jan [cited
ACCEPTED MANUSCRIPT
115
170. Mssner J, Secknus R, Meyer J, Niederau C, Adler G. Treatment of pain with pancreatic
extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter
trial. Digestion [Internet]. 1992 [cited 2017 Mar 7];53(12):5466. Available from:
PT
171. Malesci A, Gaia E, Fioretta A, Bocchia P, Ciravegna G, Cantor P, et al. No effect of long-
term treatment with pancreatic extract on recurrent abdominal pain in patients with
RI
chronic pancreatitis. Scand J Gastroenterol [Internet]. 1995 Apr [cited 2017 Mar
172. larvin M,McMohan MJ, Thomas WEG PM. Creon (enteric coated pancreatin
SC
microspheres) for the treatment of pain in chronic pancreatitis: a double-blind randomised
placebo-controlled crossover study. Gastroenterology. 1991;(100):A283.
173. Spiller RC, Trotman IF, Higgins BE, Ghatei MA, Grimble GK, Lee YC, et al. The ileal
brake--inhibition of jejunal motility after ileal fat perfusion in man. Gut [Internet]. 1984
U
Apr [cited 2017 Mar 7];25(4):36574. Available from:
AN
174. Read NW, McFarlane A, Kinsman RI, Bates TE, Blackhall NW, Farrar GB, et al. Effect
of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels
of neurotensin and enteroglucagon. Gastroenterology [Internet]. 1984 Feb [cited 2017 Mar
M

175. Lin HC, Neevel C, Chen P-S, Suh G, Chen JH. Slowing of intestinal transit by fat or
peptide YY depends on -adrenergic pathway. Am J Physiol - Gastrointest Liver Physiol
D
[Internet]. 2003 Dec [cited 2017 Mar 7];285(6):G13106. Available from:

176. Vu MK, Vecht J, Eddes EH, Biemond I, Lamers CB, Masclee AA. Antroduodenal
TE
motility in chronic pancreatitis: are abnormalities related to exocrine insufficiency? Am J

Physiol Gastrointest Liver Physiol [Internet]. 2000 Mar [cited 2017 Mar 7];278(3):G458-
66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10712266
EP
177. Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena,

antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol
[Internet]. 2002 Oct [cited 2017 Mar 7];30(6):62050. Available from:
http://journals.sagepub.com/doi/10.1080/01926230290166724
C
178. Szuster-Ciesielska A, Daniluk J, Kandefer-Szersze M. Oxidative stress in blood of

patients with alcohol-related pancreatitis. Pancreas [Internet]. 2001 Apr [cited 2017 Mar
AC

179. Hausmann DH, Porstmann T, Weber I, Hausmann S, Dummler W, Liebe S, et al. Cu/Zn-
SOD in human pancreatic tissue and pancreatic juice. Int J Pancreatol [Internet]. 1997 Dec
180. Van Gossum A, Closset P, Noel E, Cremer M, Neve J. Deficiency in antioxidant factors in
patients with alcohol-related chronic pancreatitis. Dig Dis Sci [Internet]. 1996 Jun [cited
ACCEPTED MANUSCRIPT
116
181. Basso D, Panozzo MP, Fabris C, del Favero G, Meggiato T, Fogar P, et al. Oxygen
derived free radicals in patients with chronic pancreatic and other digestive diseases. J
Clin Pathol [Internet]. 1990 May [cited 2017 Mar 7];43(5):4035. Available from:
PT
182. Braganza JM, Schofield D, Snehalatha C, Mohan V. Micronutrient antioxidant status in
tropical compared with temperate-zone chronic pancreatitis. Scand J Gastroenterol
RI
[Internet]. 1993 Dec [cited 2017 Mar 7];28(12):1098104. Available from:
183. Uden S, Schofield D, Miller PF, Day JP, Bottiglier T, Braganza JM. Antioxidant therapy
SC
for recurrent pancreatitis: biochemical profiles in a placebo-controlled trial. Aliment
Pharmacol Ther [Internet]. 1992 Apr [cited 2017 Mar 7];6(2):22940. Available from:
184. Whiteley G, Kienle A LS et al. Micronutrient antioxidant therapy in the nonsurgical
U
management of painful chronic pancreatitis: long term observation. Pancreas.
1994;(9):A807.
AN
185. Kirk GR, White JS, McKie L, Stevenson M, Young I, Clements WDB, et al. Combined
antioxidant therapy reduces pain and improves quality of life in chronic pancreatitis. J
Gastrointest Surg [Internet]. 2006 Apr [cited 2017 Mar 7];10(4):499503. Available from:
M
http://linkinghub.elsevier.com/retrieve/pii/S1091255X05006694
186. Bhardwaj P, Garg PK, Maulik SK, Saraya A, Tandon RK, Acharya SK. A Randomized
Controlled Trial of Antioxidant Supplementation for Pain Relief in Patients With Chronic
D
Pancreatitis. Gastroenterology [Internet]. 2009 Jan [cited 2017 Mar 7];136(1):149159.e2.

187. Siriwardena AK, Mason JM, Sheen AJ, Makin AJ, Shah NS. Antioxidant Therapy Does
TE
Not Reduce Pain in Patients With Chronic Pancreatitis: The ANTICIPATE Study.
Gastroenterology [Internet]. 2012 Sep [cited 2017 Mar 7];143(3):655663.e1. Available
EP
188. Garg PK. Antioxidants for chronic pancreatitis: reasons for disappointing results despite
sound principles. Gastroenterology [Internet]. 2013 Mar [cited 2017 Mar 7];144(3):e19-
20. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0016508513000127
189. Braganza JM. Limitations of patient selection and other issues in chronic pancreatitis
C
antioxidant trial. Gastroenterology [Internet]. 2013 Mar [cited 2017 Mar 14];144(3):e17-8.
AC
190. Zhou D, Wang W, Cheng X, Wei J, Zheng S. Antioxidant therapy for patients with
chronic pancreatitis: A systematic review and meta-analysis. Clin Nutr [Internet]. 2015
191. Talukdar R, Murthy HV V, Reddy DN. Role of methionine containing antioxidant
combination in the management of pain in chronic pancreatitis: a systematic review and
meta-analysis. Pancreatology [Internet]. 2015 Mar [cited 2017 Mar 7];15(2):13644.
192. Talukdar R, Lakhtakia S, Nageshwar Reddy D, Rao GV, Pradeep R, Banerjee R, et al.
ACCEPTED MANUSCRIPT
117
Ameliorating effect of antioxidants and pregabalin combination in pain recurrence after

ductal clearance in chronic pancreatitis: Results of a randomized, double blind, placebo-
controlled trial. J Gastroenterol Hepatol [Internet]. 2016 Sep [cited 2017 Mar
PT
193. Shalimar, Midha S, Hasan A, Dhingra R, Garg PK. Long-term pain relief with optimized
medical treatment including antioxidants and step-up interventional therapy in patients
RI
with chronic pancreatitis. J Gastroenterol Hepatol [Internet]. 2017 Jan [cited 2017 Mar
194. Dalal S, Bruera E. Assessing cancer pain. Curr Pain Headache Rep [Internet]. 2012 Aug
SC
http://link.springer.com/10.1007/s11916-012-0274-y
195. Twycross RG. Analgesics. Postgrad Med J [Internet]. 1984 Dec [cited 2017 Mar
U
196. Olesen AE, Olofsen E, Olesen SS, Staahl C, Andresen T, Dahan A, et al. The absorption
profile of pregabalin in chronic pancreatitis. Basic Clin Pharmacol Toxicol [Internet].
AN
http://doi.wiley.com/10.1111/j.1742-7843.2012.00914.x
197. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management.
M
Stepping up the quality of its evaluation. JAMA [Internet]. 1995 Dec 20 [cited 2017 Mar
198. Thiagarajan P, Jankowski JA. Aspirin and NSAIDs; benefits and harms for the gut. Best
D
Pract {&} Res Gastroenterol. 2012 Apr;26(2):197206.

199. Poulsen JL, Olesen SS, Malver LP, Frkjr JB, Drewes AM. Pain and chronic
pancreatitis: a complex interplay of multiple mechanisms. World J Gastroenterol
TE
[Internet]. 2013 Nov 14 [cited 2017 Mar 8];19(42):728291. Available from:

200. Olesen SS, Bouwense SAW, Wilder-Smith OHG, van Goor H, Drewes AM. Pregabalin
EP
reduces pain in patients with chronic pancreatitis in a randomized, controlled trial.

Gastroenterology [Internet]. Elsevier Inc.; 2011 Aug [cited 2017 Mar 8];141(2):53643.
201. Gurusamy KS, Lusuku C, Davidson BR. Pregabalin for decreasing pancreatic pain in
C
chronic pancreatitis. Gurusamy KS, editor. Cochrane database Syst Rev [Internet].
Chichester, UK: John Wiley & Sons, Ltd; 2016 Feb 2 [cited 2017 Mar 8];2:CD011522.
AC
Available from: http://doi.wiley.com/10.1002/14651858.CD011522.pub2

202. Drewes AM, Krarup AL, Detlefsen S, Malmstrm M-L, Dimcevski G, Funch-Jensen P.
Pain in chronic pancreatitis: the role of neuropathic pain mechanisms. Gut [Internet]. 2008
Nov 1 [cited 2017 Mar 8];57(11):161627. Available from:
203. Thorkelson G, Bielefeldt K, Szigethy E. Empirically Supported Use of Psychiatric
Medications in Adolescents and Adults with IBD. Inflamm Bowel Dis [Internet]. 2016 Jun
ACCEPTED MANUSCRIPT
118
201606000-00028
204. Xie C, Tang Y, Wang Y, Yu T, Wang Y, Jiang L, et al. Efficacy and Safety of
Antidepressants for the Treatment of Irritable Bowel Syndrome: A Meta-Analysis. Lu L,
PT
editor. PLoS One [Internet]. 2015 Aug 7 [cited 2017 Mar 8];10(8):e0127815. Available
205. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American
RI
College of Gastroenterology monograph on the management of irritable bowel syndrome
and chronic idiopathic constipation. Am J Gastroenterol [Internet]. 2014 Aug [cited 2017
Mar 8];S226; quiz S27. Available from:
SC
206. Shah E, Kim S, Chong K, Lembo A, Pimentel M. Evaluation of harm in the
pharmacotherapy of irritable bowel syndrome. Am J Med [Internet]. 2012 Apr [cited 2017
U
207. Trnblom H, Drossman DA. Centrally targeted pharmacotherapy for chronic abdominal
AN
pain. Neurogastroenterol Motil [Internet]. 2015 Apr [cited 2017 Mar 8];27(4):45567.
Available from: http://doi.wiley.com/10.1111/nmo.12509
208. Gilson AM, Maurer MA, Ryan KM, Skemp-Brown M, Husain A, Cleary JF. Ensuring
M
Patient Access to Essential Medicines While Minimizing Harmful Use: A Revised World
Health Organization Tool to Improve National Drug Control Policy. J Pain Palliat Care
Pharmacother [Internet]. 2011 Aug 30 [cited 2017 Mar 8];25(3):24651. Available from:
D
209. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic
PainUnited States, 2016. JAMA [Internet]. 2016 Apr 19 [cited 2017 Mar
TE

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464
210. Seal KH, Maguen S, Bertenthal D, Batki SL, Striebel J, Stein MB, et al. Observational
EP
Evidence for Buprenorphines Impact on Posttraumatic Stress Symptoms in Veterans

With Chronic Pain and Opioid Use Disorder. J Clin Psychiatry [Internet]. 2016 Sep 28
http://www.psychiatrist.com/jcp/article/pages/2016/v77n09/v77n0919.aspx
C
211. Likar R, Kayser H, Sittl R. Long-term management of chronic pain with transdermal
buprenorphine: a multicenter, open-label, follow-up study in patients from three short-
AC
term clinical trials. Clin Ther [Internet]. 2006 Jun [cited 2017 Mar 8];28(6):94352.
212. Drewes AM, Jensen RD, Nielsen LM, Droney J, Christrup LL, Arendt-Nielsen L, et al.
Differences between opioids: pharmacological, experimental, clinical and economical
perspectives. Br J Clin Pharmacol [Internet]. 2013 Jan [cited 2017 Mar 8];75(1):6078.
213. Drewes AM, Munkholm P, Simrn M, Breivik H, Kongsgaard UE, Hatlebakk JG, et al.
Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction
Recommendations of the Nordic Working Group. Scand J Pain [Internet]. 2016 Apr [cited
ACCEPTED MANUSCRIPT
119
2017 Mar 15];11:11122. Available from:

214. Drossman D, Szigethy E. The narcotic bowel syndrome: a recent update. Am J
PT
Gastroenterol Suppl [Internet]. 2014 Sep 10 [cited 2017 Mar 8];2(1):2230. Available
from: http://www.nature.com/doifinder/10.1038/ajgsup.2014.6
215. Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Evolving paradigms in the
RI
treatment of opioid-induced bowel dysfunction. Therap Adv Gastroenterol [Internet].
http://journals.sagepub.com/doi/10.1177/1756283X15589526
SC
216. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic
Pain--United States, 2016. JAMA [Internet]. 2016 Apr 19 [cited 2017 Mar
8];315(15):162445. Available from:
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464
U
217. Olesen SS, Juel J, Graversen C, Kolesnikov Y, Wilder-Smith OHG, Drewes AM.
Pharmacological pain management in chronic pancreatitis. World J Gastroenterol
AN
[Internet]. 2013 Nov 14 [cited 2017 Mar 8];19(42):7292. Available from:
218. Wilder-Smith CH, Hill L, Osler W, OKeefe S. Effect of tramadol and morphine on pain
M
and gastrointestinal motor function in patients with chronic pancreatitis. Dig Dis Sci
[Internet]. 1999 Jun [cited 2017 Mar 8];44(6):110716. Available from:
D
219. Sengupta JN, Su X, Gebhart GF. Kappa, but not mu or delta, opioids attenuate responses
to distention of afferent fibers innervating the rat colon. Gastroenterology [Internet]. 1996
Oct [cited 2017 Mar 8];111(4):96880. Available from:
TE
220. Eisenach JC, Carpenter R, Curry R. Analgesia from a peripherally active kappa-opioid
receptor agonist in patients with chronic pancreatitis. Pain. 2003 Jan;101(12):8995.
EP
221. Niemann T, Madsen LG, Larsen S, Thorsgaard N. Opioid treatment of painful chronic
pancreatitis. Int J Pancreatol [Internet]. 2000 Jun [cited 2017 Mar 8];27(3):23540.
222. Noppers I, Niesters M, Aarts L, Smith T, Sarton E, Dahan A. Ketamine for the treatment
C
of chronic non-cancer pain. Expert Opin Pharmacother [Internet]. 2010 Oct 9 [cited 2017
AC
223. Juel J, Olesen SS, Olesen AE, Poulsen JL, Dahan A, Wilder-Smith O, et al. Study protocol
for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain
treatment in patients with chronic pancreatitis (RESET trial). BMJ Open [Internet]. 2015
Mar 10 [cited 2017 Mar 8];5(3):e007087. Available from:
http://bmjopen.bmj.com/cgi/doi/10.1136/bmjopen-2014-007087
224. Bannwarth B, Kostine M. Biologics in the treatment of chronic pain: a new era of
therapy? Clin Pharmacol Ther [Internet]. 2015 Feb [cited 2017 Mar 8];97(2):1224.
Available from: http://doi.wiley.com/10.1002/cpt.20
ACCEPTED MANUSCRIPT
120
225. Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, et al. Nerve growth factor modulates
TRPV1 expression and function and mediates pain in chronic pancreatitis.
Gastroenterology [Internet]. 2011 Jul [cited 2017 Mar 8];141(1):3707. Available from:
PT
226. Malfertheiner P, Mayer D, Bchler M, Domnguez-Muoz JE, Schiefer B, Ditschuneit H.
Treatment of pain in chronic pancreatitis by inhibition of pancreatic secretion with
RI
octreotide. Gut [Internet]. 1995 Mar [cited 2017 Mar 8];36(3):4504. Available from:
227. Dunphy RC, Verne GN. Drug treatment options for irritable bowel syndrome: managing
SC
for success. Drugs Aging [Internet]. 2001 [cited 2017 Mar 8];18(3):20111. Available
228. Attal N, Fermanian C, Fermanian J, Lanteri-Minet M, Alchaar H, Bouhassira D.
Neuropathic pain: Are there distinct subtypes depending on the aetiology or anatomical
U
lesion? Pain [Internet]. 2008 Aug 31 [cited 2017 Jun 21];138(2):34353. Available from:
AN
229. Grosen K, Fischer IWD, Olesen AE, Drewes AM. Can quantitative sensory testing predict
responses to analgesic treatment? Eur J Pain [Internet]. 2013 Oct [cited 2017 Mar
8];17(9):126780. Available from: http://doi.wiley.com/10.1002/j.1532-
M
2149.2013.00330.x
230. Rsch T, Daniel S, Scholz M, Huibregtse K, Smits M, Schneider T, et al. Endoscopic
treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term
D
follow-up. Endoscopy [Internet]. 2002 Oct [cited 2017 Mar 8];34(10):76571. Available
from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-2002-34256
231. Ahmed Ali U, Pahlplatz JM, Nealon WH, van Goor H, Gooszen HG, Boermeester MA.
TE
Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. In:

Ahmed Ali U, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester,
UK: John Wiley & Sons, Ltd; [cited 2017 Mar 8]. p. CD007884. Available from:
EP
232. Cahen DL, Gouma DJ, Nio Y, Rauws EAJ, Boermeester MA, Busch OR, et al.
Endoscopic versus Surgical Drainage of the Pancreatic Duct in Chronic Pancreatitis. N
Engl J Med [Internet]. 2007 Feb 15 [cited 2017 Mar 14];356(7):67684. Available from:
C
233. Dte P, Ruzicka M, Zboril V, Novotn I. A Prospective, Randomized Trial Comparing
AC
Endoscopic and Surgical Therapy for Chronic Pancreatitis. Endoscopy [Internet]. 2003 Jul
234. Tadenuma H, Ishihara T, Yamaguchi T, Tsuchiya S, Kobayashi A, Nakamura K, et al.
Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for
pancreatic stones. Clin Gastroenterol Hepatol [Internet]. 2005 Nov [cited 2017 Mar
235. Farnbacher MJ, Schoen C, Rabenstein T, Benninger J, Hahn EG, Schneider HT.
Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success.
ACCEPTED MANUSCRIPT
121
Gastrointest Endosc [Internet]. 2002 Oct [cited 2017 Mar 8];56(4):5016. Available from:
http://www.mosby.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artTyp
e=abs&id=a128162
PT
236. Binmoeller KF, Jue P, Seifert H, Nam WC, Izbicki J, Soehendra N. Endoscopic pancreatic
stent drainage in chronic pancreatitis and a dominant stricture: long-term results.
Endoscopy [Internet]. 1995 Nov 17 [cited 2017 Mar 8];27(9):63844. Available from:
RI
237. Smits ME, Badiga SM, Rauws EA, Tytgat GN, Huibregtse K. Long-term results of
pancreatic stents in chronic pancreatitis. Gastrointest Endosc [Internet]. 1995 Nov [cited
SC
238. Vitale GC, Cothron K, Vitale EA, Rangnekar N, Zavaleta CM, Larson GM, et al. Role of
pancreatic duct stenting in the treatment of chronic pancreatitis. Surg Endosc [Internet].
2004 Oct 26 [cited 2017 Mar 8];18(10):14314. Available from:
U
http://link.springer.com/10.1007/s00464-003-8933-z
239. Eleftherladis N, Dinu F, Delhaye M, Le Moine O, Baize M, Vandermeeren A, et al. Long-
AN
term outcome after pancreatic stenting in severe chronic pancreatitis. Endoscopy
M
240. Farnbacher MJ, Mhldorfer S, Wehler M, Fischer B, Hahn EG, Schneider HT.
Interventional endoscopic therapy in chronic pancreatitis including temporary stenting: a
definitive treatment? Scand J Gastroenterol [Internet]. 2006 Jan 8 [cited 2017 Mar
D

241. Weber A, Schneider J, Neu B, Meining A, Born P, Schmid RM, et al. Endoscopic stent
TE
therapy for patients with chronic pancreatitis: results from a prospective follow-up study.
Pancreas [Internet]. 2007 Apr [cited 2017 Mar 8];34(3):28794. Available from:
EP
200704000-00002
242. Costamagna G, Bulajic M, Tringali A, Pandolfi M, Gabbrielli A, Spada C, et al. Multiple
stenting of refractory pancreatic duct strictures in severe chronic pancreatitis: long-term
results. Endoscopy [Internet]. 2006 Mar [cited 2017 Mar 8];38(3):2549. Available from:
C
243. Eisendrath P, Devire J. Expandable metal stents for benign pancreatic duct obstruction.
AC
Gastrointest Endosc Clin N Am [Internet]. 1999 Jul [cited 2017 Mar 8];9(3):54754.
244. Park DH, Kim M-H, Moon S-H, Lee SS, Seo D-W, Lee S-K. Feasibility and safety of
placement of a newly designed, fully covered self-expandable metal stent for refractory
benign pancreatic ductal strictures: a pilot study (with video). Gastrointest Endosc
[Internet]. 2008 Dec [cited 2017 Mar 8];68(6):11829. Available from:
245. Sauer B, Talreja J, Ellen K, Ku J, Shami VM, Kahaleh M. Temporary placement of a fully
covered self-expandable metal stent in the pancreatic duct for management of
ACCEPTED MANUSCRIPT
122
symptomatic refractory chronic pancreatitis: preliminary data (with videos). Gastrointest

Endosc [Internet]. 2008 Dec [cited 2017 Mar 8];68(6):11738. Available from:
PT
246. Moon S-H, Kim M-H, Park DH, Song TJ, Eum J, Lee SS, et al. Modified fully covered
self-expandable metal stents with antimigration features for benign pancreatic-duct
strictures in advanced chronic pancreatitis, with a focus on the safety profile and reducing
RI
migration. Gastrointest Endosc [Internet]. 2010 Jul [cited 2017 Mar 8];72(1):8691.
247. Giacino C, Grandval P, Laugier R. Fully covered self-expanding metal stents for
SC
refractory pancreatic duct strictures in chronic pancreatitis. Endoscopy [Internet]. 2012
Sep 23 [cited 2017 Mar 8];44(9):8747. Available from: http://www.thieme-
connect.de/DOI/DOI?10.1055/s-0032-1309774
248. Shen Y, Liu M, Chen M, Li Y, Lu Y, Zou X. Covered metal stent or multiple plastic stents
U
for refractory pancreatic ductal strictures in chronic pancreatitis: A systematic review.
Pancreatology [Internet]. 2014 Mar [cited 2017 Mar 8];14(2):8790. Available from:
AN
249. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shock-wave lithotripsy
of pancreatic calculi. Gastroenterology [Internet]. 1992 Feb [cited 2017 Mar
M

250. Sauerbruch T, Holl J, Sackmann M, Paumgartner G. Extracorporeal lithotripsy of
pancreatic stones in patients with chronic pancreatitis and pain: a prospective follow up
D
study. Gut [Internet]. 1992 Jul [cited 2017 Mar 8];33(7):96972. Available from:
251. Dumonceau JM, Devire J, Le Moine O, Delhaye M, Vandermeeren A, Baize M, et al.
TE
Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-
term results. Gastrointest Endosc [Internet]. 1996 Jun [cited 2017 Mar 8];43(6):54755.
EP
252. Brand B, Kahl M, Sidhu S, Nam VC, Sriram P V, Jaeckle S, et al. Prospective evaluation
of morphology, function, and quality of life after extracorporeal shockwave lithotripsy and
endoscopic treatment of chronic calcific pancreatitis. Am J Gastroenterol [Internet]. 2000
Dec [cited 2017 Mar 8];95(12):342838. Available from:
C
http://www.nature.com/doifinder/10.1111/j.1572-0241.2000.03190.x
253. Clarke B, Slivka A, Tomizawa Y, Sanders M, Papachristou GI, Whitcomb DC, et al.
AC
Endoscopic therapy is effective for patients with chronic pancreatitis. Clin Gastroenterol
Hepatol [Internet]. 2012 Jul [cited 2017 Mar 8];10(7):795802. Available from:
254. He Y-X, Xu H-W, Sun X-T, Ye Z, Wang W, Lai X-W, et al. Endoscopic management of
early-stage chronic pancreatitis based on M-ANNHEIM classification system: a
prospective study. Pancreas [Internet]. 2014 Aug [cited 2017 Mar 8];43(6):82933.
Available from:
201408000-00002
ACCEPTED MANUSCRIPT
123
255. Delhaye M, Arvanitakis M, Verset G, Cremer M, Devire J. Long-term clinical outcome

after endoscopic pancreatic ductal drainage for patients with painful chronic pancreatitis.
Clin Gastroenterol Hepatol [Internet]. 2004 Dec [cited 2017 Mar 8];2(12):1096106.
PT
256. Seven G, Schreiner MA, Ross AS, Lin OS, Gluck M, Gan SI, et al. Long-term outcomes
associated with pancreatic extracorporeal shock wave lithotripsy for chronic calcific
RI
pancreatitis. Gastrointest Endosc [Internet]. 2012 May [cited 2017 Mar 8];75(5):997
257. Ahmed Ali U, Nieuwenhuijs VB, van Eijck CH, Gooszen HG, van Dam RM, Busch OR,
SC
et al. Clinical outcome in relation to timing of surgery in chronic pancreatitis: a nomogram
to predict pain relief. Arch Surg [Internet]. 2012 Oct 1 [cited 2017 Mar 8];147(10):925
32. Available from:
http://archsurg.jamanetwork.com/article.aspx?doi=10.1001/archsurg.2012.1094
U
258. M D. Extracorporeal shock wave lithotripsy for pancreatic stones [Internet]. Up to Date.
2015 [cited 2017 Mar 16]. p. 19. Available from: Extracorporeal shock wave lithotripsy
AN
for pancreatic stones
259. Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the
management of chronic calcific pancreatitis: a meta-analysis. JOP [Internet]. 2005 Jan 13
M

260. Moole H, Jaeger A, Bechtold ML, Forcione D, Taneja D, Puli SR. Success of
D
Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management: A

Meta-Analysis and Systematic Review. Pancreas [Internet]. 2016 [cited 2017 Mar
TE
201605000-00004
261. Dumonceau J-M, Costamagna G, Tringali A, Vahedi K, Delhaye M, Hittelet A, et al.
EP
Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy
versus endoscopic treatment: a randomised controlled trial. Gut [Internet]. 2007 Apr 1
C
262. Ohara H, Hoshino M, Hayakawa T, Kamiya Y, Miyaji M, Takeuchi T, et al. Single

application extracorporeal shock wave lithotripsy is the first choice for patients with
AC
pancreatic duct stones. Am J Gastroenterol [Internet]. 1996 Jul [cited 2017 Mar
263. Inui K, Tazuma S, Yamaguchi T, Ohara H, Tsuji T, Miyagawa H, et al. Treatment of
pancreatic stones with extracorporeal shock wave lithotripsy: results of a multicenter
survey. Pancreas [Internet]. 2005 Jan [cited 2017 Mar 8];30(1):2630. Available from:
264. Suzuki Y, Sugiyama M, Inui K, Igarashi Y, Ohara H, Tazuma S, et al. Management for
pancreatolithiasis: a Japanese multicenter study. Pancreas [Internet]. 2013 May [cited
ACCEPTED MANUSCRIPT
124
201305000-00004
265. Adamek HE, Jakobs R, Buttmann A, Adamek MU, Schneider AR, Riemann JF. Long
PT
term follow up of patients with chronic pancreatitis and pancreatic stones treated with
extracorporeal shock wave lithotripsy. Gut [Internet]. 1999 Sep [cited 2017 Mar
RI
266. Ohyama H, Mikata R, Ishihara T, Tsuyuguchi T, Sakai Y, Sugiyama H, et al. Efficacy of
stone density on noncontrast computed tomography in predicting the outcome of
extracorporeal shock wave lithotripsy for patients with pancreatic stones. Pancreas
SC
[Internet]. 2015 Apr [cited 2017 Mar 8];44(3):4228. Available from:
900000000-99074
267. Schneider HT, May A, Benninger J, Rabenstein T, Hahn EG, Katalinic A, et al.
U
Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol
AN
268. Karasawa Y, Kawa S, Aoki Y, Ochi Y, Unno H, Kiyosawa K, et al. Extracorporeal shock
wave lithotripsy of pancreatic duct stones and patient factors related to stone
M
disintegration. J Gastroenterol [Internet]. 2002 May 1 [cited 2017 Mar 8];37(5):36975.

Available from: http://link.springer.com/10.1007/s005350200051
269. Tandan M, Reddy DN, Santosh D, Vinod K, Ramchandani M, Rajesh G, et al.
D
Extracorporeal shock wave lithotripsy and endotherapy for pancreatic calculi-a large
single center experience. Indian J Gastroenterol [Internet]. 2010 Jul 18 [cited 2017 Mar
8];29(4):1438. Available from: http://link.springer.com/10.1007/s12664-010-0035-y
TE
270. Milovic V, Wehrmann T, Dietrich CF, Bailey AA, Caspary WF, Braden B. Extracorporeal
shock wave lithotripsy with a transportable mini-lithotripter and subsequent endoscopic
treatment improves clinical outcome in obstructive calcific chronic pancreatitis.
EP
Gastrointest Endosc [Internet]. 2011 Dec [cited 2017 Mar 8];74(6):12949. Available
271. Kawaguchi Y, Ogawa M, Maruno A, Yuhara H, Ito H, Mine T. Strategy of Endoscopic
Pancreatic Duct Drainage for Recurrent Chronic Pancreatitis. Pancreat Disord Ther
C
[Internet]. OMICS International; 2013 [cited 2017 Mar 15];3(3). Available from:
http://www.omicsgroup.org/journals/strategy-of-endoscopic-pancreatic-duct-drainage-for-
AC
recurrent-chronic-pancreatitis-2165-7092.S3-002.php?aid=14221
272. Costamagna G, Gabbrielli A, Mutignani M, Perri V, Pandolfi M, Boscaini M, et al.
Extracorporeal shock wave lithotripsy of pancreatic stones in chronic pancreatitis:
immediate and medium-term results. Gastrointest Endosc [Internet]. 1997 Sep [cited 2017
273. Kozarek RA, Brandabur JJ, Ball TJ, Gluck M, Patterson DJ, Attia F, et al. Clinical
outcomes in patients who undergo extracorporeal shock wave lithotripsy for chronic
calcific pancreatitis. Gastrointest Endosc [Internet]. 2002 Oct [cited 2017 Mar
ACCEPTED MANUSCRIPT
125
http://www.mosby.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artTyp
e=abs&id=a128105
274. Hirota M, Asakura T, Kanno A, Kikuta K, Kume K, Hamada S, et al. Long-period
PT
pancreatic stenting for painful chronic calcified pancreatitis required higher medical costs
and frequent hospitalizations compared with surgery. Pancreas [Internet]. 2011 Aug [cited
RI
201108000-00020
275. Tandan M, Reddy DN, Talukdar R, Vinod K, Santosh D, Lakhtakia S, et al. Long-term
SC
clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific
pancreatitis. Gastrointest Endosc [Internet]. 2013 Nov [cited 2017 Mar 8];78(5):72633.
276. Cahen DL, Gouma DJ, Larame P, Nio Y, Rauws EAJ, Boermeester MA, et al. Long-term
U
outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with
chronic pancreatitis. Gastroenterology [Internet]. 2011 Nov [cited 2017 Mar
AN
277. Ponchon T, Bory RM, Hedelius F, Roubein LD, Paliard P, Napoleon B, et al. Endoscopic
M
stenting for pain relief in chronic pancreatitis: results of a standardized protocol.

Gastrointest Endosc [Internet]. 1995 Nov [cited 2017 Mar 8];42(5):4526. Available
D
278. Ishihara T, Yamaguchi T, Seza K, Tadenuma H, Saisho H. Efficacy of s-type stents for the
treatment of the main pancreatic duct stricture in patients with chronic pancreatitis. Scand
J Gastroenterol [Internet]. 2006 Jun 8 [cited 2017 Mar 8];41(6):74450. Available from:
TE
279. Rutter K, Ferlitsch A, Sautner T, Pspk A, Gtzinger P, Gangl A, et al. Hospitalization,
frequency of interventions, and quality of life after endoscopic, surgical, or conservative
EP
treatment in patients with chronic pancreatitis. World J Surg [Internet]. 2010 Nov 20
http://link.springer.com/10.1007/s00268-010-0713-z
280. Weber A, Schneider J, Neu B, Meining A, Born P, von Delius S, et al. Endoscopic stent
C
therapy in patients with chronic pancreatitis: a 5-year follow-up study. World J

Gastroenterol [Internet]. 2013 Feb 7 [cited 2017 Mar 8];19(5):71520. Available from:
AC
281. Rana M V, Candido KD, Raja O, Knezevic NN. Celiac plexus block in the management
of chronic abdominal pain. Curr Pain Headache Rep [Internet]. 2014 Feb 11 [cited 2017
Mar 8];18(2):394. Available from: http://link.springer.com/10.1007/s11916-013-0394-z
282. Kaufman M, Singh G, Das S, Concha-Parra R, Erber J, Micames C, et al. Efficacy of
endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for
managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J
Clin Gastroenterol [Internet]. 2010 Feb [cited 2017 Mar 8];44(2):12734. Available from:
ACCEPTED MANUSCRIPT
126
201002000-00013
283. Issa Y, Bruno MJ, Bakker OJ, Besselink MG, Schepers NJ, van Santvoort HC, et al.
Treatment options for chronic pancreatitis. Nat Rev Gastroenterol Hepatol [Internet]. 2014
PT
Sep 10 [cited 2017 Mar 8];11(9):55664. Available from:
284. Cuschieri A, Shimi SM, Crosthwaite G, Joypaul V. Bilateral endoscopic
RI
splanchnicectomy through a posterior thoracoscopic approach. J R Coll Surg Edinb
[Internet]. 1994 Feb [cited 2017 Mar 8];39(1):447. Available from:
SC
285. Bouwense SAW, Buscher HCJL, van Goor H, Wilder-Smith OHG. Has central
sensitization become independent of nociceptive input in chronic pancreatitis patients who
fail thoracoscopic splanchnicectomy? Reg Anesth Pain Med [Internet]. 2011 Nov [cited
U
201111000-00003
AN
286. Verhaegh BPM, van Kleef M, Geurts JW, Puylaert M, van Zundert J, Kessels AGH, et al.
Percutaneous radiofrequency ablation of the splanchnic nerves in patients with chronic
pancreatitis: results of single and repeated procedures in 11 patients. Pain Pract [Internet].
M

http://doi.wiley.com/10.1111/papr.12030
287. Kapural L, Cywinski JB, Sparks DA. Spinal cord stimulation for visceral pain from
D
chronic pancreatitis. Neuromodulation [Internet]. 2011 Sep [cited 2017 Mar 8];14(5):423-
6-7. Available from: http://doi.wiley.com/10.1111/j.1525-1403.2011.00381.x
288. Fregni F, Potvin K, Dasilva D, Wang X, Lenkinski RE, Freedman SD, et al. Clinical
TE
effects and brain metabolic correlates in non-invasive cortical neuromodulation for

visceral pain. Eur J Pain [Internet]. 2011 Jan [cited 2017 Mar 8];15(1):5360. Available
from: http://doi.wiley.com/10.1016/j.ejpain.2010.08.002
EP
289. Tsang A, Von Korff M, Lee S, Alonso J, Karam E, Angermeyer MC, et al. Common
chronic pain conditions in developed and developing countries: gender and age
differences and comorbidity with depression-anxiety disorders. J Pain [Internet]. 2008 Oct
C
290. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic
AC
pain: an examination in a nationally representative sample. Pain [Internet]. 2003 Nov

291. Ohayon MM, Schatzberg AF. Chronic pain and major depressive disorder in the general
population. J Psychiatr Res [Internet]. 2010 May [cited 2017 Mar 8];44(7):45461.
292. Arnow BA, Hunkeler EM, Blasey CM, Lee J, Constantino MJ, Fireman B, et al.
Comorbid depression, chronic pain, and disability in primary care. Psychosom Med
ACCEPTED MANUSCRIPT
127
200603000-00013
293. Wasan AD, Michna E, Edwards RR, Katz JN, Nedeljkovic SS, Dolman AJ, et al.
PT
Psychiatric Comorbidity Is Associated Prospectively with Diminished Opioid Analgesia
and Increased Opioid Misuse in Patients with Chronic Low Back Pain. Anesthesiology
[Internet]. 2015 Oct [cited 2017 Mar 8];123(4):86172. Available from:
RI
294. Fishbain DA, Pulikal A LJ et al. Chronic Pain Types Differ in Their Reported Prevalence
of Post -Traumatic Stress Disorder (PTSD) and There Is Consistent Evidence That
SC
Chronic Pain Is Associated with PTSD: An Evidence-Based Structured Systematic
Review. Pain Med. 2016;
295. Asmundson GJG, Coons MJ, Taylor S, Katz J. PTSD and the experience of pain: research
and clinical implications of shared vulnerability and mutual maintenance models. Can J
U
Psychiatry [Internet]. 2002 Dec [cited 2017 Mar 8];47(10):9307. Available from:
AN
296. Jeppe CY, Szabo CP, Smith MD. Chronic pancreatitis, depression and substance use
disorders: A not uncommon combination. S Afr Med J [Internet]. 2015 Mar [cited 2017
M
297. Barth KS, Balliet W, Pelic CM, Madan A, Malcolm R, Adams D, et al. Screening for
current opioid misuse and associated risk factors among patients with chronic
nonalcoholic pancreatitis pain. Pain Med [Internet]. 2014 Aug 1 [cited 2017 Mar
D
8];15(8):135964. Available from: https://academic.oup.com/painmedicine/article-

lookup/doi/10.1111/pme.12403
298. Jongsma MLA, Postma SAE, Souren P, Arns M, Gordon E, Vissers K, et al.
TE
Neurodegenerative properties of chronic pain: cognitive decline in patients with chronic

pancreatitis. Pant H, editor. PLoS One [Internet]. 2011 Aug 18 [cited 2017 Mar
8];6(8):e23363. Available from: http://dx.plos.org/10.1371/journal.pone.0023363
EP
299. Barrett K, Chang Y-P. Behavioral Interventions Targeting Chronic Pain, Depression, and
Substance Use Disorder in Primary Care. J Nurs Scholarsh an Off Publ Sigma Theta Tau
Int Honor Soc Nurs [Internet]. 2016 Jul [cited 2017 Mar 8];48(4):34553. Available from:
http://doi.wiley.com/10.1111/jnu.12213
C
300. Palsson OS, Whitehead WE. Psychological treatments in functional gastrointestinal

disorders: a primer for the gastroenterologist. Clin Gastroenterol Hepatol [Internet]. 2013
AC
Mar [cited 2017 Mar 8];11(3):208-16-3. Available from:

301. Thomas D-A, Maslin B, Legler A, Springer E, Asgerally A, Vadivelu N. Role of
Alternative Therapies for Chronic Pain Syndromes. Curr Pain Headache Rep [Internet].
2016 May 2 [cited 2017 Mar 8];20(5):29. Available from:
302. Ehde DM, Dillworth TM, Turner JA. Cognitive-behavioral therapy for individuals with
chronic pain: efficacy, innovations, and directions for research. Am Psychol [Internet].
ACCEPTED MANUSCRIPT
128
http://doi.apa.org/getdoi.cfm?doi=10.1037/a0035747
303. McCracken LM, Gauntlett-Gilbert J, Vowles KE. The role of mindfulness in a contextual
cognitive-behavioral analysis of chronic pain-related suffering and disability. Pain
PT
200709000-00010
RI
304. Dinges DF, Whitehouse WG, Orne EC, Bloom PB, Carlin MM, Bauer NK, et al. Self-
hypnosis training as an adjunctive treatment in the management of pain associated with
sickle cell disease. Int J Clin Exp Hypn [Internet]. 1997 Oct [cited 2017 Mar
SC
http://www.tandfonline.com/doi/abs/10.1080/00207149708416141
305. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease.
Gastroenterology [Internet]. 2013 Jan [cited 2017 Mar 8];144(1):3649. Available from:
U
http://linkinghub.elsevier.com/retrieve/pii/S001650851201493X
306. Madan A, Borckardt JJ, Barth KS, Romagnuolo J, Morgan KA, Adams DB.
AN
Interprofessional collaborative care reduces excess service utilization among individuals
with chronic pancreatitis. J Healthc Qual [Internet]. 2013 Sep [cited 2017 Mar
M
201309000-00005
307. Ballantyne JC, LaForge SK. Opioid dependence and addiction during opioid treatment of
D
chronic pain. Pain [Internet]. 2007 Jun [cited 2017 Mar 8];129(3):23555. Available from:
308. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What Percentage of Chronic
TE
Nonmalignant Pain Patients Exposed to Chronic Opioid Analgesic Therapy Develop

Abuse/Addiction and/or Aberrant Drug-Related Behaviors? A Structured Evidence-Based
Review. Pain Med [Internet]. 2008 May 1 [cited 2017 Mar 8];9(4):44459. Available
EP
309. Hjsted J, Sjgren P. Addiction to opioids in chronic pain patients: a literature review. Eur
J Pain [Internet]. 2007 Jul [cited 2017 Mar 8];11(5):490518. Available from:
http://doi.wiley.com/10.1016/j.ejpain.2006.08.004
C
310. Meana M, Pruitt SD, Dresselhaus TR. Opioid therapy for chronic pancreatitis: controlling
aberrant use through behavioral management. Gen Hosp Psychiatry [Internet]. [cited 2017
AC

311. Drossman DA, Morris CB, Edwards H, Wrennall CE, Weinland SR, Aderoju AO, et al.
Diagnosis, characterization, and 3-month outcome after detoxification of 39 patients with
narcotic bowel syndrome. Am J Gastroenterol [Internet]. 2012 Sep 19 [cited 2017 Mar
8];107(9):142640. Available from:
312. Kumar S, Ooi CY, Werlin S, Abu-El-Haija M, Barth B, Bellin MD, et al. Risk Factors
Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From
INSPPIRE. JAMA Pediatr [Internet]. 2016 Jun 1 [cited 2017 Mar 8];170(6):5629.
ACCEPTED MANUSCRIPT
129
Available from:
http://archpedi.jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2015.4955
313. Pohl JF, Limbers CA, Kay M, Harman A, Rollins M, Varni JW. Health-related quality of
PT
life in pediatric patients with long-standing pancreatitis. J Pediatr Gastroenterol Nutr
[Internet]. 2012 May [cited 2017 Mar 8];54(5):65763. Available from:
RI
201205000-00017
314. Ting J, Wilson L, Schwarzenberg SJ, Himes R, Barth B, Bellin MD, et al. Direct Costs of
Acute Recurrent and Chronic Pancreatitis in Children in the INSPPIRE Registry. J Pediatr
SC
Gastroenterol Nutr [Internet]. 2016 Mar [cited 2017 Mar 8];62(3):4439. Available from:
201603000-00021
315. Schwarzenberg SJ, Bellin M, Husain SZ, Ahuja M, Barth B, Davis H, et al. Pediatric
U
chronic pancreatitis is associated with genetic risk factors and substantial disease burden. J
Pediatr [Internet]. 2015 Apr [cited 2017 Mar 8];166(4):8906.e1. Available from:
AN
316. Fisher E, Heathcote L, Palermo TM, de C Williams AC, Lau J, Eccleston C. Systematic
Review and Meta-Analysis of Psychological Therapies for Children With Chronic Pain. J
M
Pediatr Psychol [Internet]. 2014 Sep 1 [cited 2017 Mar 8];39(8):76382. Available from:
317. Peng P, Stinson JN, Choiniere M, Dion D, Intrater H, Lefort S, et al. Dedicated
D
multidisciplinary pain management centres for children in Canada: the current status. Can
J Anaesth [Internet]. 2007 Dec [cited 2017 Mar 8];54(12):98591. Available from:
http://link.springer.com/10.1007/BF03016632
TE
318. Bender JL, Radhakrishnan A, Diorio C, Englesakis M, Jadad AR. Can pain be managed
through the Internet? A systematic review of randomized controlled trials. Pain [Internet].
2011 Aug [cited 2017 Mar 8];152(8):174050. Available from:
EP
201108000-00013
319. Fisher E, Law E, Palermo TM, Eccleston C. Psychological therapies (remotely delivered)
for the management of chronic and recurrent pain in children and adolescents. Fisher E,
C
editor. Cochrane database Syst Rev [Internet]. Chichester, UK: John Wiley & Sons, Ltd;
2015 Mar 23 [cited 2017 Mar 8];(3):CD011118. Available from:
AC
320. Heapy AA, Higgins DM, Cervone D, Wandner L, Fenton BT, Kerns RD. A Systematic
Review of Technology-assisted Self-Management Interventions for Chronic Pain:
Looking Across Treatment Modalities. Clin J Pain [Internet]. 2015 Jun [cited 2017 Mar
201506000-00002
321. Demir IE, Schorn S, Schremmer-Danninger E, Wang K, Kehl T, Giese NA, et al.
Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain
ACCEPTED MANUSCRIPT
130
in pancreatic cancer and chronic pancreatitis. Lo AW, editor. PLoS One [Internet]. 2013
Mar 28 [cited 2017 Mar 8];8(3):e60529. Available from:
PT
322. Bockman DE, Buchler M, Malfertheiner P, Beger HG. Analysis of nerves in chronic
pancreatitis. Gastroenterology [Internet]. 1988 Jun [cited 2017 Mar 8];94(6):145969.
RI
323. Yang CJ, Bliss LA, Schapira EF, Freedman SD, Ng SC, Windsor JA, et al. Systematic
review of early surgery for chronic pancreatitis: impact on pain, pancreatic function, and
re-intervention. J Gastrointest Surg [Internet]. 2014 Oct 19 [cited 2017 Mar
SC
8];18(10):18639. Available from: http://link.springer.com/10.1007/s11605-014-2571-8
324. Ahmed Ali U, Issa Y, Bruno MJ, van Goor H, van Santvoort H, Busch ORC, et al. Early
surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design
and rationale of a randomized trial. BMC Gastroenterol [Internet]. 2013 Mar 18 [cited
U
http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-13-49
AN
325. Bchler MW, Friess H, Mller MW, Wheatley AM, Beger HG. Randomized trial of
duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in
chronic pancreatitis. Am J Surg [Internet]. 1995 Jan [cited 2017 Mar 8];169(1):65-9-70.
M

326. Keck T, Adam U, Makowiec F, Riediger H, Wellner U, Tittelbach-Helmrich D, et al.
Short- and long-term results of duodenum preservation versus resection for the
D
management of chronic pancreatitis: a prospective, randomized study. Surgery [Internet].

2012 Sep [cited 2017 Mar 8];152(3 Suppl 1):S95102. Available from:
TE
327. Izbicki JR, Knoefel WT, Bloechle C, Kchler T, Khn R, Limmer JC, et al. [The status of
duodenum-preserving resection of the head of the pancreas in therapy of chronic
pancreatitis]. Zentralbl Chir [Internet]. 1995 [cited 2017 Mar 8];120(4):298305.
EP

328. Izbicki JR, Bloechle C, Broering DC, Knoefel WT, Kuechler T, Broelsch CE. Extended
drainage versus resection in surgery for chronic pancreatitis: a prospective randomized
trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic
C
head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg [Internet].

AC
329. Izbicki JR, Bloechle C, Knoefel WT, Kuechler T, Binmoeller KF, Broelsch CE.
Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A
prospective, randomized trial. Ann Surg [Internet]. 1995 Apr [cited 2017 Mar
330. Strate T, Taherpour Z, Bloechle C, Mann O, Bruhn JP, Schneider C, et al. Long-term
follow-up of a randomized trial comparing the beger and frey procedures for patients
suffering from chronic pancreatitis. Ann Surg [Internet]. 2005 Apr [cited 2017 Mar
ACCEPTED MANUSCRIPT
131
331. Kninger J, Seiler CM, Sauerland S, Wente MN, Reidel MA, Mller MW, et al.
Duodenum-preserving pancreatic head resection--a randomized controlled trial comparing
the original Beger procedure with the Berne modification (ISRCTN No. 50638764).
PT
Surgery [Internet]. 2008 Apr [cited 2017 Mar 8];143(4):4908. Available from:
332. Klaiber U, Alldinger I, Probst P, Bruckner T, Contin P, Kninger J, et al. Duodenum-
RI
preserving pancreatic head resection: 10-year follow-up of a randomized controlled trial
comparing the Beger procedure with the Berne modification. Surgery [Internet]. 2016 Jul
SC
333. Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, et al. Total
pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations
from PancreasFest. Pancreatology [Internet]. 2014 Jan [cited 2017 Mar 8];14(1):2735.
U
334. Chinnakotla S, Beilman GJ, Dunn TB, Bellin MD, Freeman ML, Radosevich DM, et al.
AN
Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation
Lessons Learned From Over 500 Cases. Ann Surg [Internet]. 2015 Oct [cited 2017 Mar
M
201510000-00007
335. Bouwense SAW, Ali UA, ten Broek RPG, Issa Y, van Eijck CH, Gooszen HG, et al. Pain
D
outcome after pancreatic surgery for pain of chronic pancreatitis: Relation to altered
central pain processing. Pancreatology [Internet]. Elsevier; 2013 Mar [cited 2017 Mar
15];13(2):e7. Available from:
TE
336. Jawad ZAR, Tsim N, Pai M, Bansi D, Westaby D, Vlavianos P, et al. Short and long-term
post-operative outcomes of duodenum preserving pancreatic head resection for chronic
EP
pancreatitis affecting the head of pancreas: a systematic review and meta-analysis. HPB
(Oxford) [Internet]. 2016 Feb [cited 2017 Mar 8];18(2):1218. Available from:
337. Riediger H, Adam U, Fischer E, Keck T, Pfeffer F, Hopt UT, et al. Long-term outcome
C
after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg [Internet]. 2007
Aug 10 [cited 2017 Mar 8];11(8):949-59-60. Available from:
AC
338. Mller MW, Friess H, Leitzbach S, Michalski CW, Berberat P, Ceyhan GO, et al.
Perioperative and follow-up results after central pancreatic head resection (Berne
technique) in a consecutive series of patients with chronic pancreatitis. Am J Surg
339. Keck T, Wellner UF, Riediger H, Adam U, Sick O, Hopt UT, et al. Long-term outcome
after 92 duodenum-preserving pancreatic head resections for chronic pancreatitis:
comparison of Beger and Frey procedures. J Gastrointest Surg [Internet]. 2010 Mar 22
ACCEPTED MANUSCRIPT
132

340. Nguyen-Tang T, Dumonceau J-M. Endoscopic treatment in chronic pancreatitis, timing,
PT
duration and type of intervention. Best Pract Res Clin Gastroenterol [Internet]. 2010 Jun
RI
341. Yang CJ, Bliss LA, Freedman SD, Sheth S, Vollmer CM, Ng SC, et al. Surgery for
chronic pancreatitis: the role of early surgery in pain management. Pancreas [Internet].
2015 Jul [cited 2017 Mar 8];44(5):81923. Available from:
SC
201507000-00021
342. Alexakis N, Connor S, Ghaneh P, Raraty M, Lombard M, Smart H, et al. Influence of
opioid use on surgical and long-term outcome after resection for chronic pancreatitis.
U
Surgery [Internet]. 2004 Sep [cited 2017 Mar 8];136(3):6008. Available from:
AN
343. Terrace JD, Paterson HM, Garden OJ, Parks RW, Madhavan KK. Results of
decompression surgery for pain in chronic pancreatitis. HPB (Oxford) [Internet]. 2007
M
344. Nealon WH, Thompson JC. Progressive loss of pancreatic function in chronic pancreatitis
is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of
D
the modified puestow procedure. Ann Surg [Internet]. 1993 May [cited 2017 Mar
8];217(5):458-66-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8489308
345. Bellin MD, Gelrud A, Arreaza-Rubin G, Dunn TB, Humar A, Morgan KA, et al. Total
TE
Pancreatectomy With Islet Autotransplantation. Ann Surg [Internet]. 2015 Jan [cited 2017
346. Demir IE, Friess H, Ceyhan GO. Neural plasticity in pancreatitis and pancreatic cancer.
EP
Nat Rev Gastroenterol Hepatol [Internet]. 2015 Oct 13 [cited 2017 Mar 8];12(11):64959.
347. Fisher A V., Sutton JM, Wilson GC, Hanseman DJ, Abbott DE, Smith MT, et al. High
readmission rates after surgery for chronic pancreatitis. Surgery [Internet]. 2014 Oct [cited
C

AC
348. Liao Z, Gao R, Wang W, Ye Z, Lai X-W, Wang X-T, et al. A systematic review on
endoscopic detection rate, endotherapy, and surgery for pancreas divisum. Endoscopy
[Internet]. 2009 May 31 [cited 2017 Mar 8];41(5):43944. Available from:
349. Seza K, Yamaguchi T, Ishihara T, Tadenema H, Tawada K, Saisho H, et al. A long-term
controlled trial of endoscopic pancreatic stenting for treatment of main pancreatic duct
stricture in chronic pancreatitis. Hepatogastroenterology [Internet]. [cited 2017 Mar
350. Boerma D, van Gulik TM, Rauws EAJ, Obertop H, Gouma DJ. Outcome of
ACCEPTED MANUSCRIPT
133
pancreaticojejunostomy after previous endoscopic stenting in patients with chronic

pancreatitis. Eur J Surg [Internet]. 2002 Jul 1 [cited 2017 Mar 8];168(4):2238. Available
from: http://journalsonline.tandf.co.uk/Index/10.1080/11024150260102834
PT
351. Howard TJ, Browne JS, Zyromski NJ, Lavu H, Baker MS, Shen C, et al. Mechanisms of
primary operative failure and results of remedial operation in patients with chronic
pancreatitis. J Gastrointest Surg [Internet]. 2008 Dec 10 [cited 2017 Mar 8];12(12):2087-
RI
95-6. Available from: http://link.springer.com/10.1007/s11605-008-0713-6
352. Talamini G, Bassi C, Falconi M, Sartori N, Salvia R, Di Francesco V, et al. Pain relapses
in the first 10 years of chronic pancreatitis. Am J Surg [Internet]. 1996 Jun [cited 2017
SC
353. Markowitz JS, Rattner DW, Warshaw AL. Failure of symptomatic relief after
pancreaticojejunal decompression for chronic pancreatitis. Strategies for salvage. Arch
Surg [Internet]. 1994 Apr [cited 2017 Mar 8];129(4):374-9-80. Available from:
U
354. Imrie CW. Management of recurrent pain following previous surgery for chronic
AN
pancreatitis. World J Surg [Internet]. [cited 2017 Mar 8];14(1):8893. Available from:
355. Demir IE, Tieftrunk E, Maak M, Friess H, Ceyhan GO. Pain mechanisms in chronic
M
pancreatitis: of a master and his fire. Langenbecks Arch Surg [Internet]. 2011 Feb 10
D
356. Lynch ME, Campbell F, Clark AJ, Dunbar MJ, Goldstein D, Peng P, et al. A systematic
review of the effect of waiting for treatment for chronic pain. Pain [Internet]. 2008 May
TE
200805000-00014
C EP
AC
ACCEPTED MANUSCRIPT
PT
RI
U SC
AN
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
PT
RI
U SC
AN
M
D
TE
EP
C
AC

Pancreatología PDF

Cargado por

Información del documento

Título original

Derechos de autor

Formatos disponibles

Compartir este documento

Compartir o incrustar documentos

Opciones para compartir

¿Le pareció útil este documento?

¿Este contenido es inapropiado?

Copyright:

Formatos disponibles

Pancreatología PDF

Cargado por

Copyright:

Formatos disponibles

Accepted Manuscript

Guidelines for the understanding and management of pain in chronic pancreatitis

Asbjrn M. Drewes, Stefan A.W. Bouwense, Claudia M. Campbell, Gralp O.

To appear in: Pancreatology

Received Date: 23 March 2017

Guidelines for the understanding and management of pain in

7. Institute of Translational Medicine, University of Liverpool, United Kingdom

Key words: Chronic pancreatitis; Pain treatment

Short title: Pain management

interventions and neuromodulation can be considered in difficult patients.

circulated around the four International Societies.

consensus was in favor of adopting a GRADE (Grading of Recommendations Assessment, Development,

Q5. Do enzymes and antioxidants influence pain in CP? (PKG, ES)

Q8. Is ESWL effective for pain treatment in CP? (CH, MD)

GRADE guidelines, as adapted for UpToDate (http://www.uptodate.com/home/grading-tutorial). In the

term was not used in the present work.

uncertainties relating to population risk.

assessment: low; Recommendation: strong; Agreement: strong)

compared, thus echoing the earlier binary classification(10).

Putative neurobiological causes of pain

similarly show functional changes suggesting a maladaptive pain response(20,2326).

Subjective Verbal Reports

One-dimensional scales (usually pain intensity)

pain pattern in time(10).

pain assessment measure in CP patients than unidimensional numeric scales alone(29).

Quantitative Sensory Testing (QST)

patients with CP(38).

Q4. What is the role of smoking and alcohol on pain treatment in CP

alcohol is associated with reduction in frequency of recurrence of pancreatitis(40,41). Pharmacological

there is no clear clinical trial data supporting positive outcomes(46).

the effect of smoking cessation on pain in patients with CP.

Pharmacological treatment: Logically, smoking cessation should be a strong recommendation. In a recent

Non-pharmacological treatment: Cognitive behavioral therapy combined with smoking cessation

given in a dosage of four to eight tablets four times a day.

handling of side effects (75).

already predisposed to peptic ulcers(77).

or indirectly by reducing anxiety and depression(80).

drugs including clonidine, benzodiazepines, anti-psychotics or cannabinoids may also be beneficial in

viscerotome) may predict the response to gabapentinoids(87).

Q7. Is endoscopical therapy effective for pain treatment in CP?

Endoscopic retrograde cholangio-pancreatography (ERCP) can achieve MPD drainage by sphincterotomy of

fragmentation with ESWL.

will probably achieve long-term favorable outcome.

1. recurrent attacks of pancreatic pain

2. moderate to marked changes in the pancreatic ductal system

3. obstructing ductal stones (minimal diameter: 2 5 mm, calcified or radiolucent)(92)

assessment: low; Recommendation: strong; Agreement: conditional)

seem to impair long term results probably due to central sensitization(105)

chronic pancreatitis patients with a possible concurrent pain relieving effect.

assessment: moderate; Recommendation: strong; Agreement: conditional)

sparing in a high-volume center with expertise in pancreatic surgery.

Q11. When is the optimal time for surgery in painful CP?

treatment (Quality assessment: low; Recommendation: weak; Agreement: strong).

decisive for the outcome.

Recommendation: strong; Agreement: weak).

Recommendation: strong; Agreement: strong).

Plus sign indicate sufficient/satisfactory effect.

Minus sign indicate insufficient effect

ESWL: extracorporal shock wave lithotrypsy

NSAID: non-steroidal anti-inflammatory drugs

TCA: tricyclic antidepressives

SNRI: serotonin-noradrenalin reuptake inhibitors

SSRI: selective serotonin reuptake inhibitors